Novel bicyclic bromodomain inhibitors

ABSTRACT

The invention relates to substituted bicyclic compounds, which are useful for inhibition of BET protein function by binding to bromodomains, pharmaceutical compositions comprising these compounds, and use of the compounds and compositions in therapy.

This application is a continuation of U.S. patent application Ser. No.16/440,350, filed Jun. 13, 2019, and now U.S. Pat. No. 10,772,892; whichis a continuation of U.S. patent application Ser. No. 15/875,678, filedJan. 19, 2018, and now U.S. Pat. No. 10,363,257; which is a continuationof U.S. patent application Ser. No. 15/486,256, filed Apr. 12, 2017, andnow U.S. Pat. No. 10,010,556; which is a division of U.S. patentapplication Ser. No. 14/977,508 filed Dec. 21, 2015, and now U.S. Pat.No. 9,663,520; which is a continuation of International PatentApplication No. PCT/US2014/043423, filed Jun. 20, 2014; which claimspriority from U.S. Provisional Patent Application No. 61/837,841, filedJun. 21, 2013. The content of each of the aforementioned applications ishereby incorporated by reference in its entirety.

The invention provides novel compounds, pharmaceutical compositionscontaining such compounds, and their use in prevention and treatment ofdiseases and conditions associated with bromodomain and extra terminaldomain (BET) proteins. Post-translational modifications (PTMs) ofhistones are involved in regulation of gene expression and chromatinorganization in eukaryotic cells. Histone acetylation at specific lysineresidues is a PTM that is regulated by histone acetylases (HATs) anddeacetylases (HDACs). Peserico, A. and C. Simone, “Physical andfunctional HAT/HDAC interplay regulates protein acetylation balance,” JBiomed Biotechnol 2011:371832 (2011). Small molecule inhibitors of HDACsand HATs are being investigated as cancer therapy. Hoshino, I. and H.Matsubara, “Recent advances in histone deacetylase targeted cancertherapy” Surg Today 40(9):809-15 (2010); Vernarecci, S., F. Tosi, and P.Filetici, “Tuning acetylated chromatin with HAT inhibitors: a novel toolfor therapy” Epigenetics 5(2):105-11 (2010); Bandyopadhyay, K., et al.,“Spermidinyl-CoA-based HAT inhibitors block DNA repair and providecancer-specific chemo- and radiosensitization,” Cell Cycle 8(17):2779-88(2009); Arif, M., et al., “Protein lysine acetylation in cellularfunction and its role in cancer manifestation,” Biochim Biophys Acta1799(10-12):702-16 (2010). Histone acetylation controls gene expressionby recruiting protein complexes that bind directly to acetylated lysinevia bromodomains. Sanchez, R. and M. M. Zhou, “The role of humanbromodomains in chromatin biology and gene transcription,” Curr OpinDrug Discov Devel 12(5):659-65 (2009). One such family, the bromodomainand extra terminal domain (BET) proteins, comprises Brd2, Brd3, Brd4,and BrdT, each of which contains two bromodomains in tandem that canindependently bind to acetylated lysines, as reviewed in Wu, S. Y. andC. M. Chiang, “The double bromodomain-containing chromatin adaptor Brd4and transcriptional regulation,” J Biol Chem 282(18):13141-5 (2007).

Interfering with BET protein interactions via bromodomain inhibitionresults in modulation of transcriptional programs that are oftenassociated with diseases characterized by dysregulation of cell cyclecontrol, inflammatory cytokine expression, viral transcription,hematopoietic differentiation, insulin transcription, and adipogenesis.Belkina, A. C. and G. V. Denis, “BET domain co-regulators in obesity,inflammation and cancer,” Nat Rev Cancer 12(7):465-77 (2012). BETinhibitors are believed to be useful in the treatment of diseases orconditions related to systemic or tissue inflammation, inflammatoryresponses to infection or hypoxia, cellular activation andproliferation, lipid metabolism, fibrosis, and the prevention andtreatment of viral infections. Belkina, A. C. and G. V. Denis, “BETdomain co-regulators in obesity, inflammation and cancer,” Nat RevCancer 12(7):465-77 (2012); Prinjha, R. K., J. Witherington, and K. Lee,“Place your BETs: the therapeutic potential of bromodomains,” TrendsPharmacol Sci 33(3):146-53 (2012).

Autoimmune diseases, which are often chronic and debilitating, are aresult of a dysregulated immune response, which leads the body to attackits own cells, tissues, and organs. Pro-inflammatory cytokines includingIL-1β, TNF-α, IL-6, MCP-1, and IL-17 are overexpressed in autoimmunedisease. IL-17 expression defines the T cell subset known as Th17 cells,which are differentiated, in part, by IL-6, and drive many of thepathogenic consequences of autoimmune disease. Thus, the IL-6/Th17 axisrepresents an important, potentially druggable target in autoimmunedisease therapy. Kimura, A. and T. Kishimoto, “IL-6: regulator ofTreg/Th17 balance,” Eur J Immunol 40(7):1830-5 (2010). BET inhibitorsare expected to have anti-inflammatory and immunomodulatory properties.Belkina, A. C. and G. V. Denis, “BET domain co-regulators in obesity,inflammation and cancer,” Nat Rev Cancer 12(7):465-77 (2012); Prinjha,R. K., J. Witherington, and K. Lee, “Place your BETs: the therapeuticpotential of bromodomains,” Trends Pharmacol Sci 33(3):146-53 (2012).BET inhibitors have been shown to have a broad spectrum ofanti-inflammatory effects in vitro including the ability to decreaseexpression of pro-inflammatory cytokines such as IL-1β, MCP-1, TNF-α,and IL-6 in activated immune cells. Mirguet, O., et al., “From ApoA1upregulation to BET family bromodomain inhibition: discovery ofI-BET151,” Bioorg Med Chem Lett 22(8):2963-7 (2012); Nicodeme, E., etal., “Suppression of inflammation by a synthetic histone mimic,” Nature468(7327):1119-23 (2010); Seal, J., et al., “Identification of a novelseries of BET family bromodomain inhibitors: binding mode and profile ofI-BET151 (GSK1210151A),” Bioorg Med Chem Lett 22(8):2968-72 (2012). Themechanism for these anti-inflammatory effects may involve BET inhibitordisruption of Brd4 co-activation of NF-κB-regulated pro-inflammatorycytokines and/or displacement of BET proteins from cytokine promoters,including IL-6. Nicodeme, E., et al., “Suppression of inflammation by asynthetic histone mimic,” Nature 468(7327):1119-23 (2010); Zhang, G., etal., “Down-regulation of NF-kappaB Transcriptional Activity in HIVassociated Kidney Disease by BRD4 Inhibition,” J Biol Chem,287(34):8840-51 (2012); Zhou, M., et al., “Bromodomain protein Brd4regulates human immunodeficiency virus transcription throughphosphorylation of CDK9 at threonine 29,” J Virol 83(2):1036-44 (2009).In addition, because Brd4 is involved in T-cell lineage differentiation,BET inhibitors may be useful in inflammatory disorders characterized byspecific programs of T cell differentiation. Zhang, W. S., et al.,“Bromodomain-Containing-Protein 4 (BRD4) Regulates RNA Polymerase IISerine 2 Phosphorylation in Human CD4+ T Cells,” J Biol Chem (2012).

The anti-inflammatory and immunomodulatory effects of BET inhibitionhave also been confirmed in vivo. A BET inhibitor prevented endotoxin-or bacterial sepsis-induced death and cecal ligation puncture-induceddeath in mice, suggesting utility for BET inhibitors in sepsis and acuteinflammatory disorders. Nicodeme, E., et al., “Suppression ofinflammation by a synthetic histone mimic,” Nature 468(7327):1119-23(2010). A BET inhibitor has been shown to ameliorate inflammation andkidney injury in HIV-1 transgenic mice, an animal model forHIV-associated nephropathy, in part through inhibition of Brd4interaction with NF-κB. Zhang, G., et al., “Down-regulation of NF-kappaBTranscriptional Activity in HIV associated Kidney Disease by BRD4Inhibition,” J Biol Chem, 287(34):8840-51 (2012). The utility of BETinhibition in autoimmune disease was demonstrated in a mouse model ofmultiple sclerosis, where BET inhibition resulted in abrogation ofclinical signs of disease, in part, through inhibition of IL-6 andIL-17. R. Jahagirdar, S. M. et al., “An Orally Bioavailable SmallMolecule RVX-297 Significantly Decreases Disease in a Mouse Model ofMultiple Sclerosis,” World Congress of Inflammation, Paris, France(2011). These results were supported in a similar mouse model where itwas shown that treatment with a BET inhibitor inhibited T celldifferentiation into pro-autoimmune Th1 and Th17 subsets in vitro, andfurther abrogated disease induction by pro-inflammatory Th1 cells.Bandukwala, H. S., et al., “Selective inhibition of CD4+ T-cell cytokineproduction and autoimmunity by BET protein and c-Myc inhibitors,” ProcNatl Acad Sci USA, 109(36):14532-7 (2012).

BET inhibitors may be useful in the treatment of a variety of chronicautoimmune inflammatory conditions. Thus, one aspect of the inventionprovides compounds, compositions, and methods for treating autoimmuneand/or inflammatory diseases by administering one or more compounds ofthe invention or pharmaceutical compositions comprising one or more ofthose compounds. Examples of autoimmune and inflammatory diseases,disorders, and syndromes that may be treated using the compounds andmethods of the invention include but are not limited to, inflammatorypelvic disease, urethritis, skin sunburn, sinusitis, pneumonitis,encephalitis, meningitis, myocarditis, nephritis (Zhang, G., et al.,“Down-regulation of NF-kappaB Transcriptional Activity in HIV associatedKidney Disease by BRD4 Inhibition,” J Biol Chem, 287(34):8840-51(2012)), osteomyelitis, myositis, hepatitis, gastritis, enteritis,dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis,agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowelsyndrome, ulcerative colitis (Prinjha, R. K., J. Witherington, and K.Lee, “Place your BETs: the therapeutic potential of bromodomains,”Trends Pharmacol Sci 33(3): 146-53 (2012)), Sjogren's disease, tissuegraft rejection, hyperacute rejection of transplanted organs, asthma,allergic rhinitis, chronic obstructive pulmonary disease (COPD),autoimmune polyglandular disease (also known as autoimmune polyglandularsyndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis,dermatomyositis, multiple sclerosis (Bandukwala, H. S., et al.,“Selective inhibition of CD4+ T-cell cytokine production andautoimmunity by BET protein and c-Myc inhibitors,” Proc Natl Acad SciUSA, 109(36):14532-7 (2012)), scleroderma, vasculitis, autoimmunehemolytic and thrombocytopenic states, Goodpasture's syndrome,atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer'sdisease, Type I diabetes (Belkina, A. C. and G. V. Denis, “BET domainco-regulators in obesity, inflammation and cancer,” Nat Rev Cancer12(7):465-77 (2012)), septic shock (Zhang, G., et al., “Down-regulationof NF-kappaB Transcriptional Activity in HIV associated Kidney Diseaseby BRD4 Inhibition,” J Biol Chem, 287(34):8840-51 (2012)), systemiclupus erythematosus (SLE) (Prinjha, R. K., J. Witherington, and K. Lee,“Place your BETs: the therapeutic potential of bromodomains,” TrendsPharmacol Sci 33(3):146-53 (2012)), rheumatoid arthritis (Denis, G. V.,“Bromodomain coactivators in cancer, obesity, type 2 diabetes, andinflammation,” Discov Med 10(55):489-99 (2010)), psoriatic arthritis,juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenicpurpura, Waldenstrom macroglobulinemia, myasthenia gravis, Hashimoto'sthyroiditis, atopic dermatitis, degenerative joint disease, vitiligo,autoimmune hypopituitarism, Guillain-Barre syndrome, Behcet's disease,uveitis, dry eye disease, scleroderma, mycosis fungoides, and Graves'disease.

BET inhibitors may be useful in the treatment of a wide variety of acuteinflammatory conditions. Thus, one aspect of the invention providescompounds, compositions, and methods for treating inflammatoryconditions including but not limited to, acute gout, giant cellarteritis, nephritis including lupus nephritis, vasculitis with organinvolvement, such as glomerulonephritis, vasculitis, including giantcell arteritis, Wegener's granulomatosis, polyarteritis nodosa, Behcet'sdisease, Kawasaki disease, and Takayasu's arteritis.

BET inhibitors may be useful in the prevention and treatment of diseasesor conditions that involve inflammatory responses to infections withbacteria, viruses, fungi, parasites, and their toxins, such as, but notlimited to sepsis, sepsis syndrome, septic shock (Nicodeme, E., et al.,“Suppression of inflammation by a synthetic histone mimic,” Nature468(7327):1119-23 (2010)), systemic inflammatory response syndrome(SIRS), multi-organ dysfunction syndrome, toxic shock syndrome, acutelung injury, adult respiratory distress syndrome (ARDS), acute renalfailure, fulminant hepatitis, burns, post-surgical syndromes,sarcoidosis, Herxheimer reactions, encephalitis, myelitis, meningitis,malaria, and SIRS associated with viral infections, such as influenza,herpes zoster, herpes simplex, and coronavirus. Belkina, A. C. and G. V.Denis, “BET domain co-regulators in obesity, inflammation and cancer,”Nat Rev Cancer 12(7):465-77 (2012). Thus, one aspect of the inventionprovides compounds, compositions, and methods for treating theseinflammatory responses to infections with bacteria, viruses, fungi,parasites, and their toxins described herein.

Cancer is a group of diseases caused by dysregulated cell proliferation.Therapeutic approaches aim to decrease the numbers of cancer cells byinhibiting cell replication or by inducing cancer cell differentiationor death, but there is still significant unmet medical need for moreefficacious therapeutic agents. Cancer cells accumulate genetic andepigenetic changes that alter cell growth and metabolism, promoting cellproliferation and increasing resistance to programmed cell death, orapoptosis. Some of these changes include inactivation of tumorsuppressor genes, activation of oncogenes, and modifications of theregulation of chromatin structure, including deregulation of histonePTMs. Watson, J. D., “Curing ‘incurable’ cancer,” Cancer Discov1(6):477-80 (2011); Morin, R. D., et al., “Frequent mutation ofhistone-modifying genes in non-Hodgkin lymphoma” Nature476(7360):298-303 (2011).

One aspect of the invention provides compounds, compositions, andmethods for treating human cancer, including, but not limited to,cancers that result from aberrant translocation or overexpression of BETproteins (e.g., NUT midline carcinoma (NMC) (French, C. A., “NUT midlinecarcinoma,” Cancer Genet Cytogenet 203(1):16-20 (2010) and B-celllymphoma (Greenwald, R. J., et al., “E mu-BRD2 transgenic mice developB-cell lymphoma and leukemia,” Blood 103(4):1475-84 (2004)). NMC tumorcell growth is driven by a translocation of the Brd4 or Brd3 gene to thenutlin 1 gene. Filippakopoulos, P., et al., “Selective inhibition of BETbromodomains,” Nature 468(7327):1067-73 (2010). BET inhibition hasdemonstrated potent antitumor activity in murine xenograft models ofNMC, a rare but lethal form of cancer. The present disclosure alsoprovides a method for treating human cancers, including, but not limitedto, cancers dependent on a member of the myc family of oncoproteinsincluding c-myc, MYCN, and L-myc. Vita, M. and M. Henriksson, “The Myconcoprotein as a therapeutic target for human cancer,” Semin Cancer Biol16(4):318-30 (2006). These cancers include Burkitt's lymphoma, acutemyelogenous leukemia, multiple myeloma, and aggressive humanmedulloblastoma. Vita, M. and M. Henriksson, “The Myc oncoprotein as atherapeutic target for human cancer,” Semin Cancer Biol 16(4):318-30(2006). Cancers in which c-myc is overexpressed may be particularlysusceptible to BET protein inhibition; it has been shown that treatmentof tumors that have activation of c-myc with a BET inhibitor resulted intumor regression through inactivation of c-myc transcription. Dawson, M.A., et al., Inhibition of BET recruitment to chromatin as an effectivetreatment for MLL-fusion leukaemia. Nature, 2011. 478(7370): p. 529-33;Delmore, J. E., et al., “BET bromodomain inhibition as a therapeuticstrategy to target c-Myc,” Cell 146(6):904-17 (2010); Mertz, J. A., etal., “Targeting MYC dependence in cancer by inhibiting BETbromodomains,” Proc Natl Acad Sci USA 108(40):16669-74 (2011); Ott, C.J., et al., “BET bromodomain inhibition targets both c-Myc and IL7R inhigh risk acute lymphoblastic leukemia,” Blood 120(14):2843-52 (2012);Zuber, J., et al., “RNAi screen identifies Brd4 as a therapeutic targetin acute myeloid leukaemia,” Nature 478(7370):524-8 (2011).

Embodiments of the invention include methods for treating human cancersthat rely on BET proteins and pTEFb (Cdk9/CyclinT) to regulate oncogenes(Wang, S. and P. M. Fischer, “Cyclin-dependent kinase 9: a keytranscriptional regulator and potential drug target in oncology,virology and cardiology,” Trends Pharmacol Sci 29(6):302-13 (2008)), andcancers that can be treated by inducing apoptosis or senescence byinhibiting Bcl2, cyclin-dependent kinase 6 (CDK6) (Dawson, M. A., etal., “Inhibition of BET recruitment to chromatin as an effectivetreatment for MLL-fusion leukaemia,” Nature 478(7370):529-33 (2011)), orhuman telomerase reverse transcriptase (hTERT). Delmore, J. E., et al.,“BET bromodomain inhibition as a therapeutic strategy to target c-Myc,”Cell 146(6):904-17 (2010); Ruden, M. and N. Puri, “Novel anticancertherapeutics targeting telomerase,” Cancer Treat Rev (2012).

BET inhibitors may be useful in the treatment of cancers including, butnot limited to, adrenal cancer, acinic cell carcinoma, acoustic neuroma,acral lentiginous melanoma, acrospiroma, acute eosinophilic leukemia,acute erythroid leukemia, acute lymphoblastic leukemia, acutemegakaryoblastic leukemia, acute monocytic leukemia, acute myeloidleukemia (Dawson, M. A., et al., “Inhibition of BET recruitment tochromatin as an effective treatment for MLL-fusion leukaemia,” Nature478(7370):529-33 (2011); Mertz, J. A., et al., “Targeting MYC dependencein cancer by inhibiting BET bromodomains,” Proc Natl Acad Sci USA108(40):16669-74 (2011); Zuber, J., et al., “RNAi screen identifies Brd4as a therapeutic target in acute myeloid leukaemia,” Nature478(7370):524-8 (2011)), adenocarcinoma, adenoid cystic carcinoma,adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adiposetissue neoplasm, adrenocortical carcinoma, adult T-cellleukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma,alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblasticfibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer,angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma,astrocytoma, atypical teratoid rhabdoid tumor, B-cell acutelymphoblastic leukemia (Ott, C. J., et al., “BET bromodomain inhibitiontargets both c-Myc and IL7R in highrisk acute lymphoblastic leukemia,”Blood 120(14):2843-52 (2012)), B-cell chronic lymphocytic leukemia,B-cell prolymphocytic leukemia, B-cell lymphoma (Greenwald, R. J., etal., “E mu-BRD2 transgenic mice develop B-cell lymphoma and leukemia,”.Blood 103(4):1475-84 (2004)), basal cell carcinoma, biliary tractcancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Browntumor, Burkitt's lymphoma (Mertz, J. A., et al., “Targeting MYCdependence in cancer by inhibiting BET bromodomains,” Proc Natl Acad SciUSA 108(40):16669-74 (2011)), breast cancer, brain cancer, carcinoma,carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloidsarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma,clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-celllymphoma, cervical cancer, colorectal cancer, Degos disease,desmoplastic small round cell tumor, diffuse large B-cell lymphoma,dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonalcarcinoma, endocrine gland neoplasm, endodermal sinus tumor,enteropathy-associated T-cell lymphoma, esophageal cancer, fetus infetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroidcancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor,gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumorof the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosiscerebri, glucagonoma, gonadoblastoma, granulosa cell tumor,gynandroblastoma, gallbladder cancer, gastric cancer, hairy cellleukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma,hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma,Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma,intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna,lethal midline carcinoma, leukemia, Leydig cell tumor, liposarcoma, lungcancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma,acute lymphocytic leukemia, acute myelogenous leukemia (Mertz, J. A., etal., “Targeting MYC dependence in cancer by inhibiting BETbromodomains,” Proc Natl Acad Sci USA 108(40):16669-74 (2011)), chroniclymphocytic leukemia, liver cancer, small cell lung cancer, non-smallcell lung cancer, MALT lymphoma, malignant fibrous histiocytoma,malignant peripheral nerve sheath tumor, malignant triton tumor, mantlecell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia,mediastinal germ cell tumor, medullary carcinoma of the breast,medullary thyroid cancer, medulloblastoma, melanoma (Miguel F. Segura,et al, “BRD4 is a novel therapeutic target in melanoma,” CancerResearch. 72(8):Supplement 1 (2012)), meningioma, Merkel cell cancer,mesothelioma, metastatic urothelial carcinoma, mixed Mullerian tumor,mixed lineage leukemia (Dawson, M. A., et al., “Inhibition of BETrecruitment to chromatin as an effective treatment for MLL-fusionleukaemia,” Nature 478(7370):529-33 (2011)), mucinous tumor, multiplemyeloma (Delmore, J. E., et al., “BET bromodomain inhibition as atherapeutic strategy to target c-Myc,” Cell 146(6):904-17 (2010)),muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma,myxosarcoma, nasopharyngeal carcinoma, neurinoma, neuroblastoma,neurofibroma, neuroma, nodular melanoma, NUT-midline carcinoma(Filippakopoulos, P., et al., “Selective inhibition of BETbromodomains,” Nature 468(7327):1067-73 (2010)), ocular cancer,oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheathmeningioma, optic nerve tumor, oral cancer, osteosarcoma, ovariancancer, Pancoast tumor, papillary thyroid cancer, paraganglioma,pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitarytumor, plasmacytoma, polyembryoma, precursor T-lymphoblastic lymphoma,primary central nervous system lymphoma, primary effusion lymphoma,primary peritoneal cancer, prostate cancer, pancreatic cancer,pharyngeal cancer, pseudomyxoma peritonei, renal cell carcinoma, renalmedullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma,Richter's transformation, rectal cancer, sarcoma, Schwannomatosis,seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signetring cell carcinoma, skin cancer, small blue round cell tumors, smallcell carcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinaltumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovialsarcoma, Sezary's disease, small intestine cancer, squamous carcinoma,stomach cancer, testicular cancer, thecoma, thyroid cancer, transitionalcell carcinoma, throat cancer, urachal cancer, urogenital cancer,urothelial carcinoma, uveal melanoma, uterine cancer, verrucouscarcinoma, visual pathway glioma, vulvar cancer, vaginal cancer,Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms' tumor.Thus, one aspect of the inventions provides compounds, compositions, andmethods for treating such cancers.

BET inhibitors may be useful in the treatment of benign proliferativeand fibrotic disorders, including benign soft tissue tumors, bonetumors, brain and spinal tumors, eyelid and orbital tumors, granuloma,lipoma, meningioma, multiple endocrine neoplasia, nasal polyps,pituitary tumors, prolactinoma, pseudotumor cerebri, seborrheickeratoses, stomach polyps, thyroid nodules, cystic neoplasms of thepancreas, hemangiomas, vocal cord nodules, polyps, and cysts, Castlemandisease, chronic pilonidal disease, dermatofibroma, pilar cyst, pyogenicgranuloma, juvenile polyposis syndrome, idiopathic pulmonary fibrosis,renal fibrosis, post-operative stricture, keloid formation, scleroderma,and cardiac fibrosis. See e.g., Tang, X et al., “Assessment of Brd4Inhibition in Idiopathic Pulmonary Fibrosis Lung Fibroblasts and in VivoModels of Lung Fibrosis,”.Am J Pathology in press (2013). Thus, oneaspect of the invention provides compounds, compositions, and methodsfor treating such benign proliferative and fibrotic disorders.

Cardiovascular disease (CVD) is the leading cause of mortality andmorbidity in the United States. Roger, V. L., et al., “Heart disease andstroke statistics—2012 update: a report from the American HeartAssociation,” Circulation 125(1):e2-e220 (2012). Atherosclerosis, anunderlying cause of CVD, is a multifactorial disease characterized bydyslipidemia and inflammation. BET inhibitors are expected to beefficacious in atherosclerosis and associated conditions because ofaforementioned anti-inflammatory effects as well as ability to increasetranscription of ApoA-I, the major constituent of HDL. Mirguet, O., etal., “From ApoA1 upregulation to BET family bromodomain inhibition:discovery of I-BET151,” Bioorg Med Chem Lett 22(8):2963-7 (2012); Chung,C. W., et al., “Discovery and characterization of small moleculeinhibitors of the BET family bromodomains,” J Med Chem 54(11):3827-38(2011). Accordingly, one aspect of the invention provides compounds,compositions, and methods for treating cardiovascular disease, includingbut not limited to atherosclerosis.

Up-regulation of ApoA-I is considered to be a useful strategy intreatment of atherosclerosis and CVD. Degoma, E. M. and D. J. Rader,“Novel HDL-directed pharmacotherapeutic strategies,” Nat Rev Cardiol8(5):266-77 (2011) BET inhibitors have been shown to increase ApoA-Itranscription and protein expression. Mirguet, O., et al., “From ApoA1upregulation to BET family bromodomain inhibition: discovery ofI-BET151,” Bioorg Med Chem Lett 22(8):2963-7 (2012); Chung, C. W., etal., “Discovery and characterization of small molecule inhibitors of theBET family bromodomains,” J Med Chem 54(11):3827-38 (2011). It has alsobeen shown that BET inhibitors bind directly to BET proteins and inhibittheir binding to acetylated histones at the ApoA-1 promoter, suggestingthe presence of a BET protein repression complex on the ApoA-1 promoter,which can be functionally disrupted by BET inhibitors. It follows that,BET inhibitors may be useful in the treatment of disorders of lipidmetabolism via the regulation of ApoA-I and HDL such ashypercholesterolemia, dyslipidemia, atherosclerosis (Degoma, E. M. andD. J. Rader, “Novel FIDL-directed pharmacotherapeutic strategies,” NatRev Cardiol 8(5):266-77 (2011)), and Alzheimer's disease and otherneurological disorders. Elliott, D. A., et al., “Apolipoproteins in thebrain: implications for neurological and psychiatric disorders,” ClinLipidol 51(4):555-573 (2010). Thus, one aspect of the invention providescompounds, compositions, and methods for treating cardiovasculardisorders by upregulation of ApoA-1.

BET inhibitors may be useful in the prevention and treatment ofconditions associated with ischemia-reperfusion injury such as, but notlimited to, myocardial infarction, stroke, acute coronary syndromes(Prinjha, R. K., J. Witherington, and K. Lee, “Place your BETs: thetherapeutic potential of bromodomains,” Trends Pharmacol Sci33(3):146-53 (2012)), renal reperfusion injury, organ transplantation,coronary artery bypass grafting, cardio-pulmonary bypass procedures,hypertension, pulmonary, renal, hepatic, gastro-intestinal, orperipheral limb embolism. Accordingly, one aspect of the inventionprovides compounds, compositions, and methods for prevention andtreatment of conditions described herein that are associated withischemia-reperfusion injury.

Obesity-associated inflammation is a hallmark of type II diabetes,insulin resistance, and other metabolic disorders. Belkina, A. C. and G.V. Denis, “BET domain co-regulators in obesity, inflammation andcancer,” Nat Rev Cancer 12(7):465-77 (2012); Denis, G. V., “Bromodomaincoactivators in cancer, obesity, type 2 diabetes, and inflammation,”Discov Med 10(55):489-99 (2010). Consistent with the ability of BETinhibitors to inhibit inflammation, gene disruption of Brd2 in miceablates inflammation and protects animals from obesity-induced insulinresistance. Wang, F., et al., “Brd2 disruption in mice causes severeobesity without Type 2 diabetes,” Biochem J 425(1):71-83 (2010). It hasbeen shown that Brd2 interacts with PPARγ and opposes itstranscriptional function. Knockdown of Brd2 in vitro promotestranscription of PPARγ-regulated networks, including those controllingadipogenesis. Denis, G. V., et al, “An emerging role forbromodomain-containing proteins in chromatin regulation andtranscriptional control of adipogenesis,” FEBS Lett 584(15):3260-8(2010). In addition Brd2 is highly expressed in pancreatic β-cells andregulates proliferation and insulin transcription. Wang, F., et al.,“Brd2 disruption in mice causes severe obesity without Type 2 diabetes,”Biochem J 425(1):71-83 (2010). Taken together, the combined effects ofBET inhibitors on inflammation and metabolism decrease insulinresistance and may be useful in the treatment of pre-diabetic and typeII diabetic individuals as well as patients with other metaboliccomplications. Belkina, A. C. and G. V. Denis, “BET domain co-regulatorsin obesity, inflammation and cancer,” Nat Rev Cancer 12(7):465-77(2012). Accordingly, one aspect of the invention provides compounds,compositions, and methods for treatment and prevention of metabolicdisorders, including but not limited to obesity-associated inflammation,type II diabetes, and insulin resistance.

Host-encoded BET proteins have been shown to be important fortranscriptional activation and repression of viral promoters. Brd4interacts with the E2 protein of human papilloma virus (HPV) to enableE2 mediated transcription of E2-target genes. Gagnon, D., et al.,“Proteasomal degradation of the papillomavirus E2 protein is inhibitedby overexpression of bromodomain-containing protein 4,” J Virol83(9):4127-39 (2009). Similarly, Brd2, Brd3, and Brd4 all bind to latentnuclear antigen 1 (LANA1), encoded by Kaposi's sarcoma-associated herpesvirus (KSHV), promoting LANA1-dependent proliferation of KSHV-infectedcells. You, J., et al., “Kaposi's sarcoma-associated herpesviruslatency-associated nuclear antigen interacts with bromodomain proteinBrd4 on host mitotic chromosomes,” J Virol 80(18):8909-19 (2006). A BETinhibitor has been shown to inhibit the Brd4-mediated recruitment of thetranscription elongation complex pTEFb to the Epstein-Barr virus (EBV)viral C promoter, suggesting therapeutic value for EBV-associatedmalignancies. Palermo, R. D., et al., “RNA polymerase II stallingpromotes nucleosome occlusion and pTEFb recruitment to driveimmortalization by Epstein-Barr virus,” PLoS Pathog 7(10):e1002334(2011). Also, a BET inhibitor reactivated HIV in models of latent T cellinfection and latent monocyte infection, potentially allowing for viraleradication by complementary anti-retroviral therapy. Zhu, J., et al.,“Reactivation of Latent HIV-1 by Inhibition of BRD4,” Cell Rep (2012);Banerjee, C., et al., “BET bromodomain inhibition as a novel strategyfor reactivation of HIV-1,” J Leukoc Biol (2012); Bartholomeeusen, K.,et al., “BET bromodomain inhibition activates transcription via atransient release of P-TEFb from 7SK snRNP,” J Biol Chem (2012); Li, Z.,et al., “The BET bromodomain inhibitor JQ1 activates HIV latency throughantagonizing Brd4 inhibition of Tat-transactivation,” Nucleic Acids Res(2012).

BET inhibitors may be useful in the prevention and treatment ofepisome-based DNA viruses including, but not limited to, humanpapillomavirus, herpes virus, Epstein-Barr virus, human immunodeficiencyvirus (Belkina, A. C. and G. V. Denis, “BET domain co-regulators inobesity, inflammation and cancer,” Nat Rev Cancer 12(7):465-77 (2012)),adenovirus, poxvirus, hepatitis B virus, and hepatitis C virus. Thus,the invention also provides compounds, compositions, and methods fortreatment and prevention of episome-based DNA virus infections describedherein.

Some central nervous system (CNS) diseases are characterized bydisorders in epigenetic processes. Brd2 haplo-insufficiency has beenlinked to neuronal deficits and epilepsy. Velisek, L., et al.,“GABAergic neuron deficit as an idiopathic generalized epilepsymechanism: the role of BRD2 haploinsufficiency in juvenile myoclonicepilepsy,” PLoS One 6(8): e23656 (2011) SNPs in variousbromodomain-containing proteins have also been linked to mentaldisorders including schizophrenia and bipolar disorders. Prinjha, R. K.,J. Witherington, and K. Lee, “Place your BETs: the therapeutic potentialof bromodomains,” Trends Pharmacol Sci 33(3):146-53 (2012). In addition,the ability of BET inhibitors to increase ApoA-1 transcription may makeBET inhibitors useful in Alzheimer's disease therapy considering thesuggested relationship between increased ApoA-1 and Alzheimer's diseaseand other neurological disorders. Elliott, D. A., et al.,“Apolipoproteins in the brain: implications for neurological andpsychiatric disorders,” Clin Lipidol 51(4):555-573 (2010). Accordingly,one aspect of the invention provides compounds, compositions, andmethods for treating such CNS diseases and disorders.

BRDT is the testis-specific member of the BET protein family which isessential for chromatin remodeling during spermatogenesis. Gaucher, J.,et al., “Bromodomain-dependent stage-specific male genome programming byBrdt,” EMBO J 31(19):3809-20 (2012); Shang, E., et al., “The firstbromodomain of Brdt, a testis-specific member of the BET sub-family ofdouble-bromodomain-containing proteins, is essential for male germ celldifferentiation,” Development 134(19):3507-15 (2007). Genetic depletionof BRDT or inhibition of BRDT interaction with acetylated histones by aBET inhibitor resulted in a contraceptive effect in mice, which wasreversible when small molecule BET inhibitors were used. Matzuk, M. M.,et al., “Small-Molecule Inhibition of BRDT for Male Contraception,” Cell150(4): 673-684 (2012); Berkovits, B. D., et al., “The testis-specificdouble bromodomain-containing protein BRDT forms a complex with multiplespliceosome components and is required for mRNA splicing and 3′-UTRtruncation in round spermatids,” Nucleic Acids Res 40(15):7162-75(2012). These data suggest potential utility of BET inhibitors as anovel and efficacious approach to male contraception. Thus, anotheraspect of the invention provides compounds, compositions, and methodsfor male contraception.

Monocyte chemotactic protein-1 (MCP-1, CCL2) plays an important role incardiovascular disease. Niu, J. and P. E. Kolattukudy, “Role of MCP-1 incardiovascular disease: molecular mechanisms and clinical implications,”Clin Sci (Lond) 117(3):95-109 (2009). MCP-1, by its chemotacticactivity, regulates recruitment of monocytes from the arterial lumen tothe subendothelial space, where they develop into macrophage foam cells,and initiate the formation of fatty streaks which can develop intoatherosclerotic plaque. Dawson, J., et al., “Targeting monocytechemoattractant protein-1 signalling in disease,” Expert Opin TherTargets 7(1):35-48 (2003). The critical role of MCP-1 (and its cognatereceptor CCR2) in the development of atherosclerosis has been examinedin various transgenic and knockout mouse models on a hyperlipidemicbackground. Boring, L., et al., “Decreased lesion formation in CCR2−/−mice reveals a role for chemokines in the initiation ofatherosclerosis,” Nature 394(6696):894-7 (1998); Gosling, J., et al.,“MCP-1 deficiency reduces susceptibility to atherosclerosis in mice thatoverexpress human apolipoprotein B,” J Clin Invest 103(6):773-8 (1999);Gu, L., et al., “Absence of monocyte chemoattractant protein-1 reducesatherosclerosis in low density lipoprotein receptor-deficient mice,” MolCell 2(2):275-81 (1998); Aiello, R. J., et al., “Monocytechemoattractant protein-1 accelerates atherosclerosis in apolipoproteinE-deficient mice,” Arterioscler Thromb Vase Biol 19(6):1518-25 (1999).These reports demonstrate that abrogation of MCP-1 signaling results indecreased macrophage infiltration to the arterial wall and decreasedatherosclerotic lesion development.

The association between MCP-1 and cardiovascular disease in humans iswell-established. Niu, J. and P. E. Kolattukudy, “Role of MCP-1 incardiovascular disease: molecular mechanisms and clinical implications,”Clin Sci (Lond) 117(3):95-109 (2009). MCP-1 and its receptor areoverexpressed by endothelial cells, smooth muscle cells, andinfiltrating monocytes/macrophages in human atherosclerotic plaque.Nelken, N. A., et al., “Monocyte chemoattractant protein-1 in humanatheromatous plaques,”. J Clin Invest 88(4):1121-7 (1991). Moreover,elevated circulating levels of MCP-1 are positively correlated with mostcardiovascular risk factors, measures of coronary atherosclerosisburden, and the incidence of coronary heart disease (CHD). Deo, R., etal., “Association among plasma levels of monocyte chemoattractantprotein-1, traditional cardiovascular risk factors, and subclinicalatherosclerosis,” J Am Coll Cardiol 44(9):1812-8 (2004). CHD patientswith among the highest levels of MCP-1 are those with acute coronarysyndrome (ACS), de Lemos, J. A., et al., “Association between plasmalevels of monocyte chemoattractant protein-1 and long-term clinicaloutcomes in patients with acute coronary syndromes,” Circulation107(5):690-5 (2003). In addition to playing a role in the underlyinginflammation associated with CHD, MCP-1 has been shown to be involved inplaque rupture, ischemic/reperfusion injury, restenosis, and hearttransplant rejection. Niu, J. and P. E. Kolattukudy, “Role of MCP-1 incardiovascular disease: molecular mechanisms and clinical implications,”Clin Sci (Lond) 117(3):95-109 (2009).

MCP-1 also promotes tissue inflammation associated with autoimmunediseases including rheumatoid arthritis (RA) and multiple sclerosis(MS). MCP-1 plays a role in the infiltration of macrophages andlymphocytes into the joint in RA, and is overexpressed in the synovialfluid of RA patients. Koch, A. E., et al., “Enhanced production ofmonocyte chemoattractant protein-1 in rheumatoid arthritis,”J ClinInvest 90(3):772-9 (1992). Blockade of MCP-1 and MCP-1 signaling inanimal models of RA have also shown the importance of MCP-1 tomacrophage accumulation and proinflammatory cytokine expressionassociated with RA. Brodmerkel, C. M., et al., “Discovery andpharmacological characterization of a novel rodent-active CCR2antagonist, INCB3344,” J Immunol 175(8):5370-8 (2005); Bruhl, H., etal., “Dual role of CCR2 during initiation and progression ofcollagen-induced arthritis: evidence for regulatory activity of CCR2+ Tcells,” J Immunol 172(2):890-8 (2004); Gong, J. H., et al., “Anantagonist of monocyte chemoattractant protein 1 (MCP-1) inhibitsarthritis in the MRL-Ipr mouse model,” J Exp Med 186(1):131-7 (1997);65. Gong, J. H., et al., “Post-onset inhibition of murine arthritisusing combined chemokine antagonist therapy,” Rheumatology (Oxford43(1): 39-42 (2004).

Overexpression of MCP-1, in the brain, cerebrospinal fluid (CSF), andblood, has also been associated with chronic and acute MS in humans.Mahad, D. J. and R. M. Ransohoff, “The role of MCP-1 (CCL2) and CCR2 inmultiple sclerosis and experimental autoimmune encephalomyelitis (EAE),”Semin Immunol 15(1):23-32 (2003). MCP-1 is overexpressed by a variety ofcell types in the brain during disease progression and contributes tothe infiltration of macrophages and lymphocytes which mediate the tissuedamage associated with MS. Genetic depletion of MCP-1 or CCR2 in theexperimental autoimmune encephalomyelitis (EAE) mouse model, a modelresembling human MS, results in resistance to disease, primarily becauseof decreased macrophage infiltration to the CNS. Fife, B. T., et al.,“CC chemokine receptor 2 is critical for induction of experimentalautoimmune encephalomyelitis,” J Exp Med 192(6):899-905 (2000); Huang,D. R., et al., “Absence of monocyte chemoattractant protein 1 in miceleads to decreased local macrophage recruitment and antigen-specific Thelper cell type 1 immune response in experimental autoimmuneencephalomyelitis,” J Exp Med 193(6):713-26 (2001).

Preclinical data have suggested that small- and large-moleculeinhibitors of MCP-1 and CCR2 have potential as therapeutic agents ininflammatory and autoimmune indications. Thus, one aspect of theinvention provides compounds, compositions, and methods for treatingcardiovascular, inflammatory, and autoimmune conditions associated withMCP-1 and CCR2.

Accordingly, the invention provides compounds that are useful forinhibition of BET protein function by binding to bromodomains,pharmaceutical compositions comprising one or more of those compounds,and use of these compounds or compositions in the treatment andprevention of diseases and conditions, including, but not limited to,cancer, autoimmune, and cardiovascular diseases. The compounds of theinvention are defined by Formula Ia or Formula IIa:

-   -   or are stereoisomers, tautomers, pharmaceutically acceptable        salts, or hydrates thereof, wherein:    -   A is selected from 5- or 6-membered monocyclic heterocycles        fused to ring B;    -   with the proviso that A cannot be substituted or unsubstituted

-   -   B is a six-membered aromatic carbocycle or heterocycle;    -   Y is selected from N, C, and CH;    -   W₁ is selected from N and CR₁;    -   W₂ is selected from N and CR₂;    -   W₃ is selected from N and CR₃;    -   W₄ and W₅ are independently selected from N, CH, and C or        alternatively, W₄ and W₅ are both C (see, e.g., Formula Ib and        Formula IIb below);    -   W₁, W₂, and W₃ may be the same or different from each other;    -   R₁ and R₂ are independently selected from hydrogen, deuterium,        alkyl, —OH, —NH₂, -thioalkyl, alkoxy, ketone, ester, carboxylic        acid, urea, carbamate, amino, amide, halogen, carbocycle,        heterocycle, sulfone, sulfoxide, sulfide, sulfonamide, and —CN;    -   R₃ is selected from hydrogen, —NH₂, —CN, —N₃, halogen, and        deuterium; or alternatively, R³ is selected from —NO₂, —OMe,        —OEt, —NHC(O)Me, NHSO₂Me, cylcoamino, cycloamido, —OH, —SO₂Me,        —SO₂Et, —CH₂NH₂, —C(O)NH₂, and —C(O)OMe;    -   X is selected from —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂O—,        —CH₂CH₂NH—, —CH₂CH₂S—, —C(O)—, —C(O)CH₂—, —C(O)CH₂CH₂—,        —CH₂C(O)—, —CH₂CH₂C(O)—, —C(O)NH—, —C(O)O—, —C(O)S—,        —C(O)NHCH₂—, —C(O)OCH₂—, —C(O)SCH₂—, where one or more hydrogen        may independently be replaced with deuterium, halogen, —CF₃,        ketone, and where S may be oxidized to sulfoxide or sulfone; or        alternatively, X may be selected from —NFH—, —CH(OH)—,        —CH(CHB)—, and hydroxyl methyl, where one or more hydrogen may        independently be replaced with deuterium, halogen, —CF₃, ketone,        and where S may be oxidized to sulfoxide or sulfone;    -   R₄ is selected from 4-7 membered carbocycles and heterocycles;        or alternatively, R₄ is a 3 membered carbocyble or heterocycle;    -   D₁ is selected from 5-membered monocyclic carbocycles and        heterocycles; or alternatively, D₁ is a monocyclic heterocycle,        where D₁ is attached to the B ring via a carbon atom that is        part of a double bond;    -   with the proviso that if R₃ is hydrogen and A is a 5-membered        ring, then D₁ cannot be

-   -   and with the proviso that if D₁ is

and R₂ and R₃ are hydrogen and R₁ is —OMe, then the A-B bicyclic ring isnot

-   -   and with the proviso that if if D₁ is

and each of R₁, R₂, R₃, are hydrogen, then the A-B bicyclic ring is not

-   -   unless the B ring is substituted;    -   and with the proviso that if each of R₁, R₂, R₃ are hydrogen,        then the A-B bicyclic ring is not

-   -   and with the proviso that if each of R₁, R₂, R₃ are hydrogen,        then the A-B bicyclic ring is not

In certain embodiments A is a five membered ring. In some embodiments Yis N or C. In some embodiments, R₁ and R₂ are independently selectedfrom hydrogen, deuterium, alkyl, —OH, —NH₂, -thioalkyl, alkoxy, ketone,ester, carboxylic acid, urea, carbamate, amino, amide, halogen, sulfone,sulfoxide, sulfide, sulfonamide, and —CN. In some embodiments, thecompound of Formula Ia is a compound of Formula Ib, i.e., wherein W₄ andW₅ of Formula I are both C.

In some embodiments, the compound of Formula IIa is a compound ofFormula IIb, i.e., wherein W₄ and W₅ of Formula I are both C.

In another aspect of the invention, a pharmaceutical compositioncomprising a compound of Formula Ia, Formula Ib, Formula IIa, and/orFormula IIb, or stereoisomer, tautomer, pharmaceutically acceptablesalt, or hydrate thereof and one or more pharmaceutically acceptablecarriers, diluents or excipients is provided.

In yet another aspect of the invention there is provided a compound ofFormula Ia, Formula Ib, Formula IIa, and/or Formula IIb, or astereoisomer, tautomer, pharmaceutically acceptable salt, or hydratethereof, or a pharmaceutical composition comprising such compound, foruse in therapy, in particular in the treatment of diseases or conditionsfor which a bromodomain inhibitor is indicated.

In yet another aspect of the invention there is provided a compound ofFormula Ia, Formula Ib, Formula IIa, and/or Formula IIb, or astereoisomer, tautomer, pharmaceutically acceptable salt, or hydratethereof in the manufacture of a medicament for the treatment of diseasesor conditions for which a bromodomain inhibitor is indicated.

Definitions

As used in the present specification, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise. The following abbreviations and terms have the indicatedmeanings throughout.

As used herein, “cardiovascular disease” refers to diseases, disordersand conditions of the heart and circulatory system that are mediated byBET inhibition. Exemplary cardiovascular diseases, includingcholesterol- or lipid-related disorders, include, but are not limitedto, acute coronary syndrome, angina, arteriosclerosis, atherosclerosis,carotid atherosclerosis, cerebrovascular disease, cerebral infarction,congestive heart failure, congenital heart disease, coronary heartdisease, coronary artery disease, coronary plaque stabilization,dyslipidemias, dyslipoproteinemias, endothelium dysfunctions, familialhypercholesterolemia, familial combined hyperlipidemia,hypoalphalipoproteinemia, hypertriglyceridemia,hyperbetalipoproteinemia, hypercholesterolemia, hypertension,hyperlipidemia, intermittent claudication, ischemia, ischemiareperfusion injury, ischemic heart diseases, cardiac ischemia, metabolicsyndrome, multi-infarct dementia, myocardial infarction, obesity,peripheral vascular disease, reperfusion injury, restenosis, renalartery atherosclerosis, rheumatic heart disease, stroke, thromboticdisorder, transitory ischemic attacks, and lipoprotein abnormalitiesassociated with Alzheimer's disease, obesity, diabetes mellitus,syndrome X, impotence, multiple sclerosis, Parkinson's disease, andinflammatory diseases.

As used herein, “inflammatory diseases” refers to diseases, disorders,and conditions that are mediated by BET inhibition. Exemplaryinflammatory diseases, include, but are not limited to, arthritis,asthma, dermatitis, psoriasis, cystic fibrosis, post transplantationlate and chronic solid organ rejection, multiple sclerosis, systemiclupus erythematosus, inflammatory bowel diseases, autoimmune diabetes,diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy,ocular inflammation, uveitis, rhinitis, ischemia-reperfusion injury,post-angioplasty restenosis, chronic obstructive pulmonary disease(COPD), glomerulonephritis, Graves disease, gastrointestinal allergies,conjunctivitis, atherosclerosis, coronary artery disease, angina, andsmall artery disease.

As used herein, “cancer” refers to diseases, disorders, and conditionsthat are mediated by BET inhibition. Exemplary cancers, include, but arenot limited to, chronic lymphocytic leukemia and multiple myeloma,follicular lymphoma, diffuse large B cell lymphoma with germinal centerphenotype, Burkitt's lymphoma, Hodgkin's lymphoma, follicular lymphomasand activated, anaplastic large cell lymphoma, neuroblastoma and primaryneuroectodermal tumor, rhabdomyosarcoma, prostate cancer, breast cancer,NMC (NUT-midline carcinoma), acute myeloid leukemia (AML), acute Blymphoblastic leukemia (B-ALL), Burkitt's Lymphoma, B-cell lymphoma,melanoma, mixed lineage leukemia, multiple myeloma, pro-myelocyticleukemia (PML), non-Hodgkin's lymphoma, neuroblastoma, medulloblastoma,lung carcinoma (NSCLC, SCLC), and colon carcinoma.

“Subject” refers to an animal, such as a mammal, that has been or willbe the object of treatment, observation, or experiment. The methodsdescribed herein may be useful for both human therapy and veterinaryapplications. In one embodiment, the subject is a human.

As used herein, “treatment” or “treating” refers to an amelioration of adisease or disorder, or at least one discernible symptom thereof. Inanother embodiment, “treatment” or “treating” refers to an ameliorationof at least one measurable physical parameter, not necessarilydiscernible by the patient. In yet another embodiment, “treatment” or“treating” refers to inhibiting the progression of a disease ordisorder, either physically, e.g., stabilization of a discerniblesymptom, physiologically, e.g., stabilization of a physical parameter,or both. In yet another embodiment, “treatment” or “treating” refers todelaying the onset of a disease or disorder. For example, treating acholesterol disorder may comprise decreasing blood cholesterol levels.

As used herein, “prevention” or “preventing” refers to a reduction ofthe risk of acquiring a given disease or disorder.

A dash that is not between two letters or symbols is used to indicate apoint of attachment for a substituent. For example, —CONH₂ is attachedthrough the carbon atom.

By “optional” or “optionally” is meant that the subsequently describedevent or circumstance may or may not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which is does not. For example, “optionally substituted aryl”encompasses both “aryl” and “substituted aryl” as defined below. It willbe understood by those skilled in the art, with respect to any groupcontaining one or more substituents, that such groups are not intendedto introduce any substitution or substitution patterns that aresterically impractical, synthetically non-feasible and/or inherentlyunstable.

As used herein, the term “hydrate” refers to a crystal form with eithera stoichiometric or non-stoichiometric amount of water is incorporatedinto the crystal structure.

The term “alkenyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon double bond, suchas a straight or branched group of 2-8 carbon atoms, referred to hereinas (C₂-C₈)alkenyl. Exemplary alkenyl groups include, but are not limitedto, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl,hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, and4-(2-methyl-3-butene)-pentenyl.

The term “alkoxy” as used herein refers to an alkyl group attached to anoxygen (—O-alkyl-). “Alkoxy” groups also include an alkenyl groupattached to an oxygen (“alkenyloxy”) or an alkynyl group attached to anoxygen (“alkynyloxy”) groups. Exemplary alkoxy groups include, but arenot limited to, groups with an alkyl, alkenyl or alkynyl group of 1-8carbon atoms, referred to herein as (C₁-C₈)alkoxy. Exemplary alkoxygroups include, but are not limited to methoxy and ethoxy.

The term “alkyl” as used herein refers to a saturated straight orbranched hydrocarbon, such as a straight or branched group of 1-8 carbonatoms, referred to herein as (C₁-C₈)alkyl. Exemplary alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, andoctyl.

The term “alkynyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon triple bond, suchas a straight or branched group of 2-8 carbon atoms, referred to hereinas (C₂-C₈)alkynyl. Exemplary alkynyl groups include, but are not limitedto, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl,4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl.

The term “amide” as used herein refers to the form —NR_(a)C(O)(R_(b))—or —C(O)NR_(b)R_(c), wherein R_(a), R_(b), and R_(c) are eachindependently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl,cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. The amidecan be attached to another group through the carbon, the nitrogen,R_(b), or R_(c). The amide also may be cyclic, for example R_(b), andR_(c), may be joined to form a 3- to 8-membered ring, such as 5- or6-membered ring. The term “amide” encompasses groups such assulfonamide, urea, ureido, carbamate, carbamic acid, and cyclic versionsthereof. The term “amide” also encompasses an amide group attached to acarboxy group, e.g., -amide-COOH or salts such as -amide-COONa, an aminogroup attached to a carboxy group (e.g., -amino-COOH or salts such as-amino-COONa).

The term “amine” or “amino” as used herein refers to the form—NR_(d)R_(e) or —N(R_(d))R_(e)—, where R_(d) and R_(e) are independentlyselected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, carbamate,cycloalkyl, haloalkyl, heteroaryl, heterocycle, and hydrogen. The aminocan be attached to the parent molecular group through the nitrogen. Theamino also may be cyclic, for example any two of R_(d) and R_(e) may bejoined together or with the N to form a 3- to 12-membered ring (e.g.,morpholino or piperidinyl). The term amino also includes thecorresponding quaternary ammonium salt of any amino group. Exemplaryamino groups include alkylamino groups, wherein at least one of R_(d) orR_(e) is an alkyl group. In some embodiments Rd and Re each may beoptionally substituted with hydroxyl, halogen, alkoxy, ester, or amino.

The term “aryl” as used herein refers to a mono-, bi-, or othermulti-carbocyclic, aromatic ring system. The aryl group can optionallybe fused to one or more rings selected from aryls, cycloalkyls, andheterocyclyls. The aryl groups of this present disclosure can besubstituted with groups selected from alkoxy, aryloxy, alkyl, alkenyl,alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano,cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl,sulfonyl, sulfonic acid, sulfonamide, and thioketone. Exemplary arylgroups include, but are not limited to, phenyl, tolyl, anthracenyl,fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fusedcarbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. Exemplary arylgroups also include, but are not limited to a monocyclic aromatic ringsystem, wherein the ring comprises 6 carbon atoms, referred to herein as“(C₆)aryl.”

The term “arylalkyl” as used herein refers to an alkyl group having atleast one aryl substituent (e.g., -aryl-alkyl-). Exemplary arylalkylgroups include, but are not limited to, arylalkyls having a monocyclicaromatic ring system, wherein the ring comprises 6 carbon atoms,referred to herein as “(C₆)arylalkyl.”

The term “carbamate” as used herein refers to the form—R_(g)OC(O)N(R_(h))—, —R_(g)OC(O)N(R_(h))R_(i)—, or —OC(O)NR_(h)R_(i),wherein R_(g), R_(h), and R_(i) are each independently selected fromalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl,heteroaryl, heterocyclyl, and hydrogen. Exemplary carbamates include,but are not limited to, arylcarbamates or heteroaryl carbamates (e.g.,wherein at least one of R_(g), R_(h), and R_(i) are independentlyselected from aryl or heteroaryl, such as pyridine, pyridazine,pyrimidine, and pyrazine).

The term “carbocycle” as used herein refers to an aryl or cycloalkylgroup.

The term “carboxy” as used herein refers to —COOH or its correspondingcarboxylate salts (e.g., —COONa). The term carboxy also includes“carboxycarbonyl,” e.g. a carboxy group attached to a carbonyl group,e.g., —C(O)—COOH or salts, such as —C(O)—COONa.

The term “cyano” as used herein refers to —CN.

The term “cycloalkoxy” as used herein refers to a cycloalkyl groupattached to an oxygen.

The term “cycloalkyl” as used herein refers to a saturated orunsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of3-12 carbons, or 3-8 carbons, referred to herein as “(C₃-C₈)cycloalkyl,”derived from a cycloalkane. Exemplary cycloalkyl groups include, but arenot limited to, cyclohexanes, cyclohexenes, cyclopentanes, andcyclopentenes. Cycloalkyl groups may be substituted with alkoxy,aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate,sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.Cycloalkyl groups can be fused to other cycloalkyl saturated orunsaturated, aryl, or heterocyclyl groups.

The term “dicarboxylic acid” as used herein refers to a group containingat least two carboxylic acid groups such as saturated and unsaturatedhydrocarbon dicarboxylic acids and salts thereof. Exemplary dicarboxylicacids include alkyl dicarboxylic acids. Dicarboxylic acids may besubstituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino,aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether,formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen,hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl,sulfonic acid, sulfonamide and thioketone. Dicarboxylic acids include,but are not limited to succinic acid, glutaric acid, adipic acid,suberic acid, sebacic acid, azelaic acid, maleic acid, phthalic acid,aspartic acid, glutamic acid, malonic acid, fumaric acid, (+)/(−)-malicacid, (+)/(−) tartaric acid, isophthalic acid, and terephthalic acid.Dicarboxylic acids further include carboxylic acid derivatives thereof,such as anhydrides, imides, hydrazides (for example, succinic anhydrideand succinimide).

The term “ester” refers to the structure —C(O)O—, —C(O)O—R_(j)—,—R_(k)C(O)O—R_(j)—, or —R_(k)C(O)O—, where O is not bound to hydrogen,and R_(j) and R_(k) can independently be selected from alkoxy, aryloxy,alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, cycloalkyl,ether, haloalkyl, heteroaryl, and heterocyclyl. R_(k) can be a hydrogen,but R_(j) cannot be hydrogen. The ester may be cyclic, for example thecarbon atom and R_(j), the oxygen atom and R_(k), or R_(j) and R_(k) maybe joined to form a 3- to 12-membered ring. Exemplary esters include,but are not limited to, alkyl esters wherein at least one of Rj or Rk isalkyl, such as —O—C(O)-alkyl, —C(O)—O-alkyl-, and -alkyl-C(O)—O-alkyl-.Exemplary esters also include aryl or heteoraryl esters, e.g. wherein atleast one of Rj or Rk is a heteroaryl group such as pyridine,pyridazine, pyrimidine and pyrazine, such as a nicotinate ester.Exemplary esters also include reverse esters having the structure—R_(k)C(O)O—, where the oxygen is bound to the parent molecule.Exemplary reverse esters include succinate, D-argininate, L-argininate,L-lysinate and D-lysinate. Esters also include carboxylic acidanhydrides and acid halides.

The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I.

The term “haloalkyl” as used herein refers to an alkyl group substitutedwith one or more halogen atoms. “Haloalkyls” also encompass alkenyl oralkynyl groups substituted with one or more halogen atoms.

The term “heteroaryl” as used herein refers to a mono-, bi-, ormulti-cyclic, aromatic ring system containing one or more heteroatoms,for example 1-3 heteroatoms, such as nitrogen, oxygen, and sulfur.Heteroaryls can be substituted with one or more substituents includingalkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate,sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.Heteroaryls can also be fused to non-aromatic rings. Illustrativeexamples of heteroaryl groups include, but are not limited to,pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl,pyrazolyl, imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl,pyrimidilyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl,phenyl, isoxazolyl, and oxazolyl. Exemplary heteroaryl groups include,but are not limited to, a monocyclic aromatic ring, wherein the ringcomprises 2-5 carbon atoms and 1-3 heteroatoms, referred to herein as“(C₂-C₅)heteroaryl.”

The terms “heterocycle,” “heterocyclyl,” or “heterocyclic” as usedherein refer to a saturated or unsaturated 3-, 4-, 5-, 6- or 7-memberedring containing one, two, or three heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur. Heterocycles can be aromatic(heteroaryls) or non-aromatic. Heterocycles can be substituted with oneor more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl,amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl,ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl,hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl,sulfonic acid, sulfonamide and thioketone. Heterocycles also includebicyclic, tricyclic, and tetracyclic groups in which any of the aboveheterocyclic rings is fused to one or two rings independently selectedfrom aryls, cycloalkyls, and heterocycles. Exemplary heterocyclesinclude acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl,benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl,dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl,homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl,isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl,morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl,piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl,pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl,pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxaloyl,tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl,tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl,thienyl, thiomorpholinyl, thiopyranyl, and triazolyl.

The terms “hydroxy” and “hydroxyl” as used herein refer to —OH.

The term “hydroxyalkyl” as used herein refers to a hydroxy attached toan alkyl group.

The term “hydroxyaryl” as used herein refers to a hydroxy attached to anaryl group.

The term “ketone” as used herein refers to the structure —C(O)—Rn (suchas acetyl, —C(O)CH₃) or —R_(n)—C(O)—R_(o)—. The ketone can be attachedto another group through R_(n) or R_(o). R_(n) or R_(o) can be alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl, or R_(n) or R_(o)can be joined to form a 3- to 12-membered ring.

The term “monoester” as used herein refers to an analogue of adicarboxylic acid wherein one of the carboxylic acids is functionalizedas an ester and the other carboxylic acid is a free carboxylic acid orsalt of a carboxylic acid. Examples of monoesters include, but are notlimited to, to monoesters of succinic acid, glutaric acid, adipic acid,suberic acid, sebacic acid, azelaic acid, oxalic and maleic acid.

The term “phenyl” as used herein refers to a 6-membered carbocyclicaromatic ring. The phenyl group can also be fused to a cyclohexane orcyclopentane ring. Phenyl can be substituted with one or moresubstituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide,amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester,ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl,ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid,sulfonamide and thioketone.

The term “thioalkyl” as used herein refers to an alkyl group attached toa sulfur (—S-alkyl-).

“Alkyl,” “alkenyl,” “alkynyl”, “alkoxy”, “amino” and “amide” groups canbe optionally substituted with or interrupted by or branched with atleast one group selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl,amide, amino, aryl, arylalkyl, carbamate, carbonyl, carboxy, cyano,cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydroxyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl,sulfonic acid, sulfonamide, thioketone, ureido and N. The substituentsmay be branched to form a substituted or unsubstituted heterocycle orcycloalkyl.

As used herein, a suitable substitution on an optionally substitutedsubstituent refers to a group that does not nullify the synthetic orpharmaceutical utility of the compounds of the present disclosure or theintermediates useful for preparing them. Examples of suitablesubstitutions include, but are not limited to: C₁₋₈ alkyl, alkenyl oralkynyl; C₁₋₆ aryl, C₂₋₅ heteroaryl; C₃₇ cycloalkyl; C₁₋₈ alkoxy; C₆aryloxy; —CN; —OH; oxo; halo, carboxy; amino, such as —NH(C₁₋₈ alkyl),—N(C₁₋₈ alkyl)₂, —NH((C₆)aryl), or —N((C₆)aryl)₂; formyl; ketones, suchas —CO(C₁₋₈ alkyl), —CO((C₆ aryl) esters, such as —CO₂(C₁₋₈ alkyl) and—CO₂ (C₆ aryl). One of skill in art can readily choose a suitablesubstitution based on the stability and pharmacological and syntheticactivity of the compound of the present disclosure.

The term “pharmaceutically acceptable carrier” as used herein refers toany and all solvents, dispersion media, coatings, isotonic andabsorption delaying agents, and the like, that are compatible withpharmaceutical administration. The use of such media and agents forpharmaceutically active substances is well known in the art. Thecompositions may also contain other active compounds providingsupplemental, additional, or enhanced therapeutic functions.

The term “pharmaceutically acceptable composition” as used herein refersto a composition comprising at least one compound as disclosed hereinformulated together with one or more pharmaceutically acceptablecarriers.

The term “pharmaceutically acceptable prodrugs” as used hereinrepresents those prodrugs of the compounds of the present disclosurethat are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, commensurate with a reasonablebenefit/risk ratio, and effective for their intended use, as well as thezwitterionic forms, where possible, of the compounds of the presentdisclosure. A discussion is provided in Higuchi et al., “Prodrugs asNovel Delivery Systems,” ACS Symposium Series, Vol. 14, and in Roche, E.B., ed. Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

The term “pharmaceutically acceptable salt(s)” refers to salts of acidicor basic groups that may be present in compounds used in the presentcompositions. Compounds included in the present compositions that arebasic in nature are capable of forming a wide variety of salts withvarious inorganic and organic acids. The acids that may be used toprepare pharmaceutically acceptable acid addition salts of such basiccompounds are those that form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, including but notlimited to sulfate, citrate, matate, acetate, oxalate, chloride,bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate,isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate,tannate, pantothenate, bitartrate, ascorbate, succinate, maleate,gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,benzoate, glutamate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds includedin the present compositions that include an amino moiety may formpharmaceutically acceptable salts with various amino acids, in additionto the acids mentioned above. Compounds included in the presentcompositions, that are acidic in nature are capable of forming basesalts with various pharmacologically acceptable cations. Examples ofsuch salts include alkali metal or alkaline earth metal salts and,particularly, calcium, magnesium, sodium, lithium, zinc, potassium, andiron salts.

The compounds of the disclosure may contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asgeometric isomers, enantiomers or diastereomers. The term“stereoisomers” when used herein consist of all geometric isomers,enantiomers or diastereomers. These compounds may be designated by thesymbols “R” or “S,” depending on the configuration of substituentsaround the stereogenic carbon atom. The present disclosure encompassesvarious stereoisomers of these compounds and mixtures thereof.Stereoisomers include enantiomers and diastereomers. Mixtures ofenantiomers or diastereomers may be designated “(±)” in nomenclature,but the skilled artisan will recognize that a structure may denote achiral center implicitly.

Individual stereoisomers of compounds of the present disclosure can beprepared synthetically from commercially available starting materialsthat contain asymmetric or stereogenic centers, or by preparation ofracemic mixtures followed by resolution methods well known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and liberation of the optically pureproduct from the auxiliary, (2) salt formation employing an opticallyactive resolving agent, or (3) direct separation of the mixture ofoptical enantiomers on chiral chromatographic columns. Stereoisomericmixtures can also be resolved into their component stereoisomers bywell-known methods, such as chiral-phase gas chromatography,chiral-phase high performance liquid chromatography, crystallizing thecompound as a chiral salt complex, or crystallizing the compound in achiral solvent. Stereoisomers can also be obtained fromstereomerically-pure intermediates, reagents, and catalysts bywell-known asymmetric synthetic methods.

Geometric isomers can also exist in the compounds of the presentdisclosure. The present disclosure encompasses the various geometricisomers and mixtures thereof resulting from the arrangement ofsubstituents around a carbon-carbon double bond or arrangement ofsubstituents around a carbocyclic ring. Substituents around acarbon-carbon double bond are designated as being in the “Z” or “E”configuration wherein the terms “Z” and “E” are used in accordance withIUPAC standards. Unless otherwise specified, structures depicting doublebonds encompass both the E and Z isomers.

Substituents around a carbon-carbon double bond alternatively can bereferred to as “cis” or “trans,” where “cis” represents substituents onthe same side of the double bond and “trans” represents substituents onopposite sides of the double bond. The arrangements of substituentsaround a carbocyclic ring are designated as “cis” or “trans.” The term“cis” represents substituents on the same side of the plane of the ringand the term “trans” represents substituents on opposite sides of theplane of the ring. Mixtures of compounds wherein the substituents aredisposed on both the same and opposite sides of plane of the ring aredesignated “cis/trans.”

The compounds disclosed herein may exist as tautomers and bothtautomeric forms are intended to be encompassed by the scope of thepresent disclosure, even though only one tautomeric structure isdepicted.

EXEMPLARY EMBODIMENTS OF THE INVENTION

The invention provides compounds and pharmaceutical compositioncomprising one or more of those compounds wherein the structure of thecompound is defined by Formula Ia, Formula Ib, Formula IIa, and/orFormula IIb:

or is a stereoisomer, tautomer, pharmaceutically acceptable salt, orhydrate thereof,wherein:

A is selected from optionally substituted 5- or -6 membered monocyclicheterocycles fused to ring B,

with the proviso that A cannot be substituted or unsubstituted

B is a six-membered aromatic carbocycle or heterocycle;

Y is selected from N and C;

W₁ is selected from N and CR₁;

W₂ is selected from N and CR₂;

W₃ is selected from N and CR₃;

W₄ and W₅, if present, are independently selected from N, CH, and C;

W₁, W₂, and W₃ may be the same or different from each other;

X is selected from —NH—, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂O—,—CH₂CH₂NH—, —CH₂CH₂S—, —C(O)—, —C(O)CH₂—, —C(O)CH₂CH₂—, —CH₂C(O)—,—CH₂CH₂C(O)—, —C(O)NH—, —C(O)O—, —C(O)S—, —C(O)NHCH₂—, —C(O)OCH₂—,—C(O)SCH₂—, —CH(OH)—, and —CH(CHs)— where one or more hydrogen mayindependently be replaced with deuterium, hydroxymethyl, halogen, —CF₃,ketone, and where S may be oxidized to sulfoxide or sulfone;

R₄ is selected from 3-7 membered carbocycles and heterocycles;

D₁ is selected from 5-membered monocyclic heterocycles, where D₁ isattached to the B ring via a carbon atom that is part of a doublebondwithin the D₁ ring.

R₁ and R₂ are independently selected from hydrogen, deuterium, alkyl,—OH, —NH₂, -thioalkyl, alkoxy, ketone, ester, carboxylic acid, urea,carbamate, amino, amide, halogen, sulfone, sulfoxide, sulfide,sulfonamide, and —CN;

R₃ is selected from hydrogen, —NH₂, —CN, —N₃, halogen, deuterium, —NO₂,—OMe, —OEt, —NHC(O)Me, NHSO₂Me, cylcoamino, cycloamido, —OH, —SO₂Me,—SO₂Et, —CH₂NH₂, —C(O)NH₂, and —C(O)OMe;

with the proviso that if R₃ is hydrogen and A is a 5-membered ring, thenD₁ cannot be

and with the proviso that if D₁ is

and R₂ and R₃ are hydrogen and R₁ is —OMe, then the A-B bicyclic ring isnot

and with the proviso that if if D₁ is

and each of R₁, R₂, R₃, are hydrogen, then the A-B bicyclic ring is not

unless the B ring is substituted;

and with the proviso that if each of R₁, R₂, R₃ are hydrogen, then theA-B bicyclic ring is not

and with the proviso that if each of R₁, R₂, R₃ are hydrogen, then theA-B bicyclic ring is not

In some embodiments, the A ring a compound of any one of Formula Ia, Ib,IIa, or IIb or stereoisomer, tautomer, pharmaceutically acceptable salt,or hydrate thereof is optionally substituted with Z, wherein Z isselected from hydrogen, deuterium, —NH₂, amino (such as —NH(C₁-C₅),—N(C₁-C₅)₂, —NHPh, —NHBn, —NHpyridyl, —NHheterocycle(C₄-C₆),—NHcarbocycle(C₄-C₆)), alkyl(C₁-C₆), thioalkyl(C₁-C₆), alkenyl(C₁-C₆),and alkoxy(C₁-C₆). In some embodiments, Z is selected from

-Me, —CF₃, -Et, CH₃CH₂O—, CF₃CH₂—, —SMe, —SOMe, —SO₂Me, —CN,

In some embodiments, compounds of any one of Formula Ia, Ib, IIa, or IIbor stereoisomer, tautomer, pharmaceutically acceptable salt, or hydratethereof, are selected from

which may be optionally substituted with groups independently selectedfrom hydrogen, deuterium, —NH₂, amino (such as NH(C₁-C₅), carbocycle(C₁-C₅)₂, —NHPh, —NHBn, —NHpyridyl, —NHheterocycle(C₄-C₆),—NHcarbocycle(C₄-C₆)), heterocycle(C₄-C₆), carbocycle(C₄-C₆), halogen,—CN, —OH, —CF₃, alkyl(C₁-C₆), thioalkyl(C₁-C₆), alkenyl(C₁-C₆), andalkoxy(C₁-C₆); wherein X, R₄, and D₁ are as defined for any embodimentdisclosed herein.

In some embodiments, the compounds of any one of Formula Ia, Ib, IIa, orIIb or stereoisomer, tautomer, pharmaceutically acceptable salt, orhydrate thereof, are selected from

which may be optionally substituted with groups independently selectedfrom hydrogen, deuterium, —NH₂, amino (such as —NH(C₁-C₅), —N(C₁-C₅)₂,—NHPh, —NHBn, —NHpyridyl, —NHheterocycle(C₄-C₆), —NHcarbocycle(C₄-C₆),heterocycle(C₄-C₆), carbocycle(C₄-C₆), halogen, —CN, —OH, —CF₃,alkyl(C₁-C₆), thioalkyl(C₁-C₆), alkenyl(C₁-C₆), and alkoxy(C₁-C₆);wherein X, R₄, and D₁ are as defined for any embodiment disclosedherein.

In some embodiments, the compounds of any one of Formula Ia, Ib, IIa, orIIb or stereoisomer, tautomer, pharmaceutically acceptable salt, orhydrate thereof, are selected from

which may be optionally substituted with groups independently selectedfrom hydrogen, deuterium, —NH₂, amino (such as —NH(C₁-C₅), —N(C₁-C₅)₂,—NHPh, —NHBn, —NHpyridyl, —NHheterocycle(C₄-C₆), —NHcarbocycle(C₄-C₆)),heterocycle(C₄-C₆), carbocycle(C₄-C₆), halogen, —CN, —OH, —CF₃,alkyl(C₁-C₆), thioalkyl(C₁-C₆), alkenyl(C₁-C₆), and alkoxy(C₁-C₆);wherein X, R₄, and D₁ are as defined for any embodiment disclosedherein.

In some embodiments, compounds of any one of Formula Ia, Ib, IIa, or IIbor stereoisomer, tautomer, pharmaceutically acceptable salt, or hydratethereof, are selected from

which may be optionally substituted with groups independently selectedfrom hydrogen, deuterium, —NH₂, amino (such as —NH(C₁-C₅), —N(C₁-C₅)₂,—NHPh, —NHBn, —NHpyridyl, —NHheterocycle(C₄-C₆), —NHcarbocycle(C₄-C₆)),heterocycle(C₄-C₆), carbocycle(C₄-C₆), halogen, —CN, —OH, —CF₃,alkyl(C₁-C₆), thioalkyl(C₁-C₆), alkenyl(C₁-C₆), and alkoxy(C₁-C₆);wherein the definition of X, R₄, and D₁ are as defined for anyembodiment disclosed herein.

In some embodiments, compounds of any one of Formula Ia, Ib, IIa, or IIbor stereoisomer, tautomer, pharmaceutically acceptable salt, or hydratethereof, is selected from

wherein Z is selected from hydrogen, deuterium, —NH₂, amino (such as—NH(C₁-C₅), —N(C₁-C₅)₂, —NHPh, —NHBn, —NHpyridyl, —NHheterocycle(C₄-C₆),—NHcarbocycle(C₄-C₆)), alkyl(C₁-C₆), thioalkyl(C₁-C₆), alkenyl(C₁-C₆),and alkoxy(C₁-C₆); carboxyl;

D₁ is

X is selected from —CH₂— and —CH(CHs)—; and

R₄ is a phenyl ring optionally substituted with groups independentlyselected with one or more groups independently selected from deuterium,alkyl(C₁-C₄), alkoxy(C₁-C₄), halogen, —CF₃, CN, and -thioalkyl(C₁-C₄),wherein each alkyl, alkoxy, and thioalkyl may be optionally substitutedwith F, Cl, or Br.

In certain embodiments, R₄ is a phenyl ring is optionally substitutedwith one or more alkyl(C₁-C₄) selected from methyl, ethyl, propyl,isopropyl, and butyl; alkoxy(C₁-C₄), selected from methoxy, ethoxy, andisopropoxy; halogen selected from F and Cl; and thioalkyl(C₁-C₄)selected from —SMe, —SEt, —SPr, and —Sbu.

In some embodiments, the A-B bicyclic ring in the compound of any one ofFormula Ia, Ib, IIa, or IIb or stereoisomer, tautomer, pharmaceuticallyacceptable salt, or hydrate thereof, is selected from

wherein Z is selected from hydrogen, deuterium, —NH₂, amino (such as—NH(C₁-C₅), —N(C₁-C₅)₂, —NHPh, —NHBn, —NHpyridyl, —NHheterocycle(C₄-C₆),—NHcarbocycle(C₄-C₆)), alkyl(C₁-C₆), thioalkyl(C₁-C₆), alkenyl(C₁-C₆),and alkoxy(C₁-C₆).

In some embodiments, the A-B bicyclic ring in the compound of any one ofFormula Ia, Formula Ib, Formula IIa, and Formula IIb or stereoisomer,tautomer, pharmaceutically acceptable salt, or hydrate thereof, isselected from

In some embodiments, the A-B bicyclic ring in the compound of any one ofFormula Ia, Formula Ib, Formula IIa, and Formula IIb or stereoisomer,tautomer, pharmaceutically acceptable salt, or hydrate thereof, isselected from, but not limited to

which may be optionally substituted with groups independently selectedfrom hydrogen, deuterium, —NH₂, amino (such as —NH(C₁-C₅), —N(C₁-C₅)₂,—NHPh, —NHBn, —NHpyridyl, —NHheterocycle(C₄-C₇), —NHcarbocycle(C₄-C₇)),heterocycle(C₄-C₇), carbocycle(C₄-C₇), halogen, —CN, —OH, —CF₃, sulfone,sulfoxide, alkyl(C₁-C₆), thioalkyl(C₁-C₆), Alkenyl(C₁-C₆),alkoxy(C₁-C₆), ketone(C₁-C₆), ester, urea, carboxylic acid, carbamate,amide(C₁-C₆), oxo, and thio-oxo.

In some embodiments of any of Formula Ia, Formula Ib, Formula IIa, andFormula IIb, or stereoisomer, tautomer, pharmaceutically acceptablesalt, or hydrate thereof, the A-B bicyclic ring, is selected from

which may be optionally substituted with groups independently selectedfrom hydrogen, deuterium, —NH₂, amino (such as —NH(C₁-C₅), —N(C₁-C₅)₂,—NHPh, —NHBn, —NHpyridyl, —NHheterocycle(C₄-C₇), —NHcarbocycle(C₄-C₇)),heterocycle(C₄-C₇), carbocycle(C₄-C₇), halogen, —CN, —OH, —CF₃, sulfone,sulfoxide, alkyl(C₁-C₆), thioalkyl(C₁-C₆), Alkenyl(C₁-C₆),alkoxy(C₁-C₆), ketone(C₁-C₆), ester, urea, carboxylic acid, carbamate,amide(C₁-C₆), oxo, and thio-oxo.

In some embodiments, the A-B bicyclic ring in the compound of any one ofFormula Ia, Formula Ib, Formula IIa, and Formula IIb or stereoisomer,tautomer, pharmaceutically acceptable salt, or hydrate thereof, isselected from

which may be optionally substituted with groups independently selectedfrom hydrogen, deuterium, —NH₂, amino (such as —NH(C₁-C₅), —N(C₁-C₅)₂,—NHPh, —NHBn, —NHpyridyl, —NHheterocycle(C₄-C₇), —NHcarbocycle(C₄-C₇)),heterocycle(C₄-C₇), carbocycle(C₄-C₇), halogen, —CN, —OH, —CF₃, sulfone,sulfoxide, alkyl(C₁-C₆), thioalkyl(C₁-C₆), Alkenyl(C₁-C₆),alkoxy(C₁-C₆), ketone(C₁-C₆), ester, urea, carboxylic acid, carbamate,amide(C₁-C₆), oxo, and thio-oxo.

In some embodiments, the A-B bicyclic ring in the compound of any one ofFormula Ia, Formula Ib, Formula IIa, and Formula IIb or stereoisomer,tautomer, pharmaceutically acceptable salt, or hydrate thereof, isselected from

which may be optionally substituted with groups independently selectedfrom hydrogen, deuterium, —NH₂, amino (such as —NH(C₁-C₅), —N(C₁-C₅)₂,—NHPh, —NHBn, —NHpyridyl, —NHheterocycle(C₄-C₇), —NHcarbocycle(C₄-C₇)),heterocycle(C₄-C₇), carbocycle(C₄-C₇), halogen, —CN, —OH, —CF₃, sulfone,sulfoxide, sulfonamide, alkyl(C₁-C₆), thioalkyl(C₁-C₆), alkenyl(C₁-C₆),alkoxy(C₁-C₆), ketone(C₁-C₆), ester, urea, carboxylic acid, carbamate,amide(C₁-C₆), oxo, and thio-oxo.

In some embodiments, the A-B bicyclic ring in the compound of any one ofFormula Ia, Formula Ib, Formula IIa, and Formula IIb or stereoisomer,tautomer, pharmaceutically acceptable salt, or hydrate thereof, isselected from

which may be optionally substituted with groups independently selectedfrom hydrogen, deuterium, —NH₂, amino (such as —NH(C₁-C₅), —N(C₁-C₅)₂,—NHPh, —NHBn, —NHpyridyl, —NHheterocycle(C₄-C₇), —NHcarbocycle(C₄-C₇)),heterocycle(C₄-C₇), carbocycle(C₄-C₇), halogen, —CN, —OH, —CF₃, sulfone,sulfoxide, sulfonamide, alkyl(C₁-C₆), thioalkyl(C₁-C₆), alkenyl(C₁-C₆),alkoxy(C₁-C₆), ketone(C₁-C₆), ester, urea, carboxylic acid, carbamate,amide(C₁-C₆), oxo, and thio-oxo.

In some embodiments, the A ring in the compound of any one of FormulaIa, Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is selected from5-membered heterocycles fused to the B ring.

In some embodiments, Y in the compound of any one of Formula Ia, FormulaIb, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is nitrogen.

In some embodiments, D₁ in the compound of any one of Formula I, FormulaIa, or Formula II or stereoisomer, tautomer, pharmaceutically acceptablesalt, or hydrate thereof, is selected from an 5-membered monocyclicheterocycle, such as, but not limited to:

which is optionally substituted with hydrogen, deuterium,alkyl(C₁-C₄)(such as methyl, ethyl, propyl, isopropyl, butyl),alkoxy(C₁-C₄) (such as methoxy, ethoxy, isopropoxy), amino (such as—NH₂, —NHMe, —NHEt, —NHiPr, —NHBu —NMe₂, NMeEt, —NEt₂, —NEtBu,—NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as —NHC(O)Me,—NHC(O)Et, —C(O)NHMe, —C(O)NEt₂, —C(O)NiPr), —CF₃, CN, —N₃, ketone(C₁-C₄) (such as acetyl, —C(O)Et, —C(O)Pr), —S(O)Alkyl(C₁-C₄) (such as—S(O)Me, —S(O)Et), —SO₂alkyl(C₁-C₄) (such as —SO₂Me, —SO₂Et, —SO₂Pr),-thioalkyl(C₁-C₄) (such as —SMe, —SEt, —SPr, —SBu), —COOH, and/or ester(such as —C(O)OMe, —C(O)OEt, —C(O)OBu), each of which may be optionallysubstituted with hydrogen, F, Cl, Br, —OH, —NH₂, —NHMe, —OMe, —SMe, oxo,and/or thio-oxo.

In some embodiments, D₁ in the compound of any one of Formula Ia, Ib,IIa, or IIb or stereoisomer, tautomer, pharmaceutically acceptable salt,or hydrate thereof, is a monocyclic heterocycle optionally substitutedwith hydrogen, deuterium, alkyl(C₁-C₄)(such as methyl, ethyl, propyl,isopropyl, butyl), alkoxy(C₁-C₄) (such as methoxy, ethoxy, isopropoxy),amino (such as —NH₂, —NHMe, —NHEt, —NHiPr, —NHBu —NMe₂, NMeEt, —NEt₂,—NEtBu, —NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as—NHC(O)Me, —NHC(O)Et, —C(O)NHMe, —C(O)NEt₂, —C(O)NiPr), —CF₃, CN, —N₃,ketone (C₁-C₄) (such as acetyl, —C(O)Et, —C(O)Pr), —S(O)Alkyl(C₁-C₄)(such as —S(O)Me, —S(O)Et), —SO₂alkyl(C₁-C₄) (such as —SO₂Me, —SO₂Et,—SO₂Pr), -thioalkyl(C₁-C₄) (such as —SMe, —SEt, —SPr, —SBu), —COOH,and/or ester (such as —C(O)OMe, —C(O)OEt, —C(O)OBu), each of which maybe optionally substituted with hydrogen, F, Cl, Br, —OH, —NH₂, —NHMe,—OMe, —SMe, oxo, and/or thio-oxo.

In some embodiments, D₁ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is selected from a5-membered monocyclic heterocycle containing one oxygen and one or twonitrogens, where the heterocycle is connected to the rest of themolecule via a carbon-carbon bond, and which is optionally substitutedwith hydrogen, deuterium, alkyl(C₁-C₄)(such as methyl, ethyl, propyl,isopropyl, butyl), alkoxy(C₁-C₄) (such as methoxy, ethoxy, isopropoxy),amino (such as —NH₂, —NHMe, —NHEt, —NHiPr, —NHBu —NMe₂, NMeEt, —NEt₂,—NEtBu, —NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as—NHC(O)Me, —NHC(O)Et, —C(O)NHMe, —C(O)NEt₂, —C(O)NiPr), —CF₃, CN, —N₃,ketone (C₁-C₄) (such as acetyl, —C(O)Et, —C(O)Pr), —S(O)Alkyl(C₁-C₄)(such as —S(O)Me, —S(O)Et), —SO₂alkyl(C₁-C₄) (such as —SO₂Me, —SO₂Et,—SO₂Pr), -thioalkyl(C₁-C₄) (such as —SMe, —SEt, —SPr, —SBu), —COOH,and/or ester (such as —C(O)OMe, —C(O)OEt, —C(O)OBu), each of which maybe optionally substituted with hydrogen, F, Cl, Br, —OH, —NH₂, —NHMe,—OMe, —SMe, oxo, and/or thio-oxo.

In some embodiments, D₁ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is an isoxazoleoptionally substituted with hydrogen, deuterium, alkyl(C₁-C₄)(such asmethyl, ethyl, propyl, isopropyl, butyl), alkoxy(C₁-C₄) (such asmethoxy, ethoxy, isopropoxy), amino (such as —NH₂, —NHMe, —NHEt, —NHiPr,—NHBu —NMe₂, NMeEt, —NEt₂, —NEtBu, —NHC(O)NHalkyl), halogen (such as F,Cl), amide (such as —NHC(O)Me, —NHC(O)Et, —C(O)NHMe, —C(O)NEt₂,—C(O)NiPr), —CF₃, CN, —N₃, ketone (C₁-C₄) (such as acetyl, —C(O)Et,—C(O)Pr), —S(O)Alkyl(C₁-C₄) (such as —S(O)Me, —S(O)Et), —SO₂alkyl(C₁-C₄)(such as —SO₂Me, —SO₂Et, —SO₂Pr), -thioalkyl(C₁-C₄) (such as —SMe, —SEt,—SPr, —SBu), —COOH, and/or ester (such as —C(O)OMe, —C(O)OEt, —C(O)OBu),each of which may be optionally substituted with hydrogen, F, Cl, Br,—OH, —NH₂, —NHMe, —OMe, —SMe, oxo, and/or thio-oxo.

In some embodiments, D₁ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is selected froman 5-membered monocyclic heterocycle, which is optionally substitutedwith hydrogen, deuterium, Alkyl(C₁-C₄), (such as methyl, ethyl, propyl),each of which may be optionally substituted with hydrogen, —OH, —F, and—NH₂.

In some embodiments, D₁ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is selected from a5-membered monocyclic heterocycle containing one oxygen and one or twonitrogens, where the heterocycle is connected to the rest of themolecule via a carbon-carbon bond, and which is optionally substitutedwith hydrogen, deuterium, Alkyl(C₁-C₄), (such as methyl, ethyl, propyl),each of which may be optionally substituted with hydrogen, —OH, —F, and—NH₂.

In some embodiments, D₁ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is an isoxazole orpyrazole optionally substituted with hydrogen, deuterium, Alkyl(C₁-C₄),(such as methyl, ethyl, propyl), each of which may be optionallysubstituted with hydrogen, —OH, —F, and —NH₂.

In some embodiments, D₁ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof is

In some embodiments, D₁ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof is In someembodiments, D₁ in the compound of Formula Ia, Formula Ib, Formula IIa,and Formula IIb or stereoisomer, tautomer, pharmaceutically acceptablesalt, or hydrate thereof is

In some embodiments, W₁ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof is CR₁.

In some embodiments, W₂ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof is CR₂.

In some embodiments, at least one of W₁ and W₂ in the compound of anyone of Formula Ia, Formula Ib, Formula IIa, and Formula IIb orstereoisomer, tautomer, pharmaceutically acceptable salt, or hydratethereof, is nitrogen.

In some embodiments, W₁ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is CH.

In some embodiments, W₂ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is CR₂, where R₂is selected from hydrogen, deuterium, —OH, —NH₂, methyl, halogen, and—CN.

In some embodiments, W₂ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is CH.

In some embodiments, W₄ and W₅ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof are carbon.

In some embodiments, at least one of W₄ and W₅ in the compound of anyone of Formula Ia, Formula Ib, Formula IIa, and Formula IIb orstereoisomer, tautomer, pharmaceutically acceptable salt, or hydratethereof, is nitrogen.

In some embodiments, W₃ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is nitrogen.

In some embodiments, W₃ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof is CR₃, where R³ isselected from hydrogen, —NH₂, and halogen.

In some embodiments, R³ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof is selected fromhydrogen and —NH₂.

In some embodiments, R³ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is —NH₂.

In some embodiments, X in the compound of any one of Formula I, FormulaIa, or Formula II or stereoisomer, tautomer, pharmaceutically acceptablesalt, or hydrate thereof, is selected from —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH₂CH₂O—, —CH₂CH₂NH—, —CH₂CH₂S—, —C(O)—, —C(O)NH—, —C(O)O—, —C(O)S—,where one or more hydrogen may independently be replaced with deuterium,halogen, and where S may be oxidized to sulfoxide or sulfone.

In some embodiments, X in the compound of any one of Formula I, FormulaIa, or Formula II or stereoisomer, tautomer, pharmaceutically acceptablesalt, or hydrate thereof, is selected from —CH₂— and —C(O)—.

In some embodiments, X is selected from —CH₂—, —CH(CH₃)—, —CH(OH)—,—NH—, CH₂CH₂—, where one or more hydrogen may independently be replacedwith deuterium or halogen.

In some embodiments, X is selected from —CH₂—, CH(CH₃)—, and —NH—, whereone or more hydrogen may independently be replaced with deuterium orhalogen.

In some embodiments, X is selected from —CH₂—, — CH(CH₃)—, where one ormore hydrogen may independently be replaced with deuterium or halogen.

In some embodiments, X in the compound of any one of Formula Ia, FormulaIb, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is —CH₂—.

In some embodiments, R₁ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is selected fromhydrogen, deuterium, alkyl, —OH, —NH₂, -thioalkyl, alkoxy, ketone,ester, carboxylic acid, urea, carbamate, amino, amide, halogen,carbocycle, heterocycle, sulfone, sulfoxide, sulfide, sulfonamide, andand —CN.

In some embodiments, R₂ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is selected fromhydrogen, deuterium, alkyl, —OH, —NH₂, -thioalkyl, alkoxy, ketone,ester, carboxylic acid, urea, carbamate, amino, amide, halogen,carbocycle, heterocycle, sulfone, sulfoxide, sulfide, sulfonamide, andand —CN.

In some embodiments, R₁ and R₂ in the compound of any one of Formula I,Formula Ia, or stereoisomer, tautomer, pharmaceutically acceptable salt,or hydrate thereof are independently selected from hydrogen, deuterium,alkyl, —NH₂, -thioalkyl, alkoxy, amino, amide, halogen, carbocycle,heterocycle, and —CN.

In some embodiments, R₁ and R₂ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, are independentlyselected from hydrogen, deuterium, alkyl(C₁-C₆), —NH₂,-thioalkyl(C₁-C₆), alkoxy(C₁-C₆), amino, and amide.

In some embodiments, R₁ and R₂ are hydrogen.

In some embodiments, at least one of R₁, R₂, and R₃ in the compound ofany one of Formula Ia, Formula Ib, Formula IIa, and Formula IIb orstereoisomer, tautomer, pharmaceutically acceptable salt, or hydratethereof, is not hydrogen.

In some embodiments, R₄ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is selected from5-6 membered carbocycles and heterocycles.

In some embodiments, R₄ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is selected from5-6 membered heterocycles.

In some embodiments, R₄ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is selected from5-6 membered heterocycles containing 1 or 2 nitrogens, such asunsubstituted and substituted pyrimidyl rings, which are optionallysubstituted with groups independently selected from hydrogen, deuterium,alkyl(C₁-C₄)(such as methyl, ethyl, propyl, isopropyl, butyl),alkoxy(C₁-C₄) (such as methoxy, ethoxy, isopropoxy), amino (such as—NH₂, —NHMe, —NHEt, —NHiPr, —NHBu —NMe₂, NMeEt, —NEt₂, —NEtBu,—NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as —NHC(O)Me,—NHC(O)Et, —C(O)NHMe, —C(O)NEt₂, —C(O)NiPr), —CF₃, CN, —N₃, ketone(C₂-C₄) (such as acetyl, —C(O)Et, —C(O)Pr), —S(O)Alkyl(C₁-C₄) (such as—S(O)Me, —S(O)Et), —SO₂alkyl(C₁-C₄) (such as —SO₂Me, —SO₂Et, —SO₂Pr),-thioalkyl(C₁-C₄) (such as —SMe, —SEt, —SPr, —SBu), carboxyl (such as—COOH), and/or ester (such as —C(O)OMe, —C(O)OEt, —C(O)OBu), each ofwhich may be optionally substituted with hydrogen, F, Cl, Br, —OH, —NH₂,—NHMe, —OMe, —SMe, oxo, and/or thio-oxo.

In some embodiments, R₄ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is selected from6-membered heterocycles containing at least one nitrogen, such asunsubstituted and substituted pyridyl rings, which are optionallysubstituted with groups independently selected from hydrogen, deuterium,alkyl(C₁-C₄)(such as methyl, ethyl, propyl, isopropyl, butyl),alkoxy(C₁-C₄) (such as methoxy, ethoxy, isopropoxy), amino (such as—NH₂, —NHMe, —NHEt, —NHiPr, —NHBu —NMe₂, NMeEt, —NEt₂, —NEtBu,—NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as —NHC(O)Me,—NHC(O)Et, —C(O)NHMe, —C(O)NEt₂, —C(O)NiPr), —CF₃, CN, —N₃, ketone(C₂-C₄) (such as acetyl, —C(O)Et, —C(O)Pr), —S(O)Alkyl(C₁-C₄) (such as—S(O)Me, —S(O)Et), —SO₂alkyl(C₁-C₄) (such as —SO₂Me, —SO₂Et, —SO₂Pr),-thioalkyl(C₁-C₄) (such as —SMe, —SEt, —SPr, —SBu), carboxyl (such as—COOH), and/or ester (such as —C(O)OMe, —C(O)OEt, —C(O)OBu), each ofwhich may be optionally substituted with hydrogen, F, Cl, Br, —OH, —NH₂,—NHMe, —OMe, —SMe, oxo, and/or thio-oxo.

In some embodiments, R₄ in the compound of any one of Formula I, FormulaIa, or Formula II or stereoisomer, tautomer, pharmaceutically acceptablesalt, or hydrate thereof, is selected from

In some embodiments, R₄ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is an isoxazole orpyrazole optionally substituted with groups independently selected fromhydrogen, deuterium, alkyl(C₁-C₄)(such as methyl, ethyl, propyl,isopropyl, butyl), alkoxy(C₁-C₄) (such as methoxy, ethoxy, isopropoxy),amino (such as —NH₂, —NHMe, —NHEt, —NHiPr, —NHBu —NMe₂, NMeEt, —NEt₂,—NEtBu, —NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as—NHC(O)Me, —NHC(O)Et, —C(O)NHMe, —C(O)NEt₂, —C(O)NiPr), —CF₃, CN, —N₃,ketone (C₁-C₄) (such as acetyl, —C(O)Et, —C(O)Pr), —S(O)Alkyl(C₁-C₄)(such as —S(O)Me, —S(O)Et), —SO₂alkyl(C₁-C₄) (such as —SO₂Me, —SO₂Et,—SO₂Pr), -thioalkyl(C₁-C₄) (such as —SMe, —SEt, —SPr, —SBu), carboxyl(such as —COOH), and/or ester (such as —C(O)OMe, —C(O)OEt, —C(O)OBu),each of which may be optionally substituted with hydrogen, F, Cl, Br,—OH, —NH₂, —NHMe, —OMe, —SMe, oxo, and/or thio-oxo.

In some embodiments, R₄ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is selected from a5-membered heterocycle containing one or two nitrogens.

In some embodiments, R₄ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is selected from5-6 membered carbocycles, such as a phenyl ring optionally substitutedwith groups independently selected from hydrogen, deuterium,alkyl(C₁-C₄)(such as methyl, ethyl, propyl, isopropyl, butyl),alkoxy(C₁-C₄) (such as methoxy, ethoxy, isopropoxy), amino (such as—NH₂, —NHMe, —NHEt, —NHiPr, —NHBu —NMe₂, NMeEt, —NEt₂, —NEtBu,—NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as —NHC(O)Me,—NHC(O)Et, —C(O)NHMe, —C(O)NEt₂, —C(O)NiPr), —CF₃, CN, —N₃, ketone(C₁-C₄) (such as acetyl, —C(O)Et, —C(O)Pr), —S(O)Alkyl(C₁-C₄) (such as—S(O)Me, —S(O)Et), —SO₂alkyl(C₁-C₄) (such as —SO₂Me, —SO₂Et, —SO₂Pr),-thioalkyl(C₁-C₄) (such as —SMe, —SEt, —SPr, —SBu), carboxyl (such as—COOH), and/or ester (such as —C(O)OMe, —C(O)OEt, —C(O)OBu), each ofwhich may be optionally substituted with hydrogen, F, Cl, Br, —OH, —NH₂,—NHMe, —OMe, —SMe, oxo, and/or thio-oxo.

In some embodiments, R₄ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is a phenyl ringoptionally substituted with groups independently selected from hydrogen,deuterium, alkyl(C₁-C₄)(such as methyl, ethyl, propyl, isopropyl,butyl), alkoxy(C₁-C₄) (such as methoxy, ethoxy, isopropoxy), amino (suchas —NH₂, —NHMe, —NHEt, —NHiPr, —NHBu —NMe₂, NMeEt, —NEt₂, —NEtBu,—NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as —NHC(O)Me,—NHC(O)Et, —C(O)NHMe, —C(O)NEt₂, —C(O)NiPr), —CF₃, CN, —N₃, ketone(C₁-C₄) (such as acetyl, —C(O)Et, —C(O)Pr), —S(O)Alkyl(C₁-C₄) (such as—S(O)Me, —S(O)Et), —SO₂alkyl(C₁-C₄) (such as —SO₂Me, —SO₂Et, —SO₂Pr),-thioalkyl(C₁-C₄) (such as —SMe, —SEt, —SPr, —SBu), carboxyl (such as—COOH), and/or ester (such as —C(O)OMe, —C(O)OEt, —C(O)OBu), each ofwhich may be optionally substituted with hydrogen, F, Cl, Br, —OH, —NH₂,—NHMe, —OMe, —SMe, oxo, and/or thio-oxo.

In some embodiments, R₄ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is selected froman aryl optionally substituted with groups independently selected fromhydrogen, deuterium, alkyl(C₁-C₄)(such as methyl, ethyl, propyl,isopropyl, butyl), alkoxy(C₁-C₄) (such as methoxy, ethoxy, isopropoxy),amino (such as —NH₂, —NHMe, —NHEt, —NHiPr, —NHBu —NMe₂, NMeEt, —NEt₂,—NEtBu, —NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as—NHC(O)Me, —NHC(O)Et, —C(O)NHMe, —C(O)NEt₂, —C(O)NiPr), —CF₃, CN, —N₃,ketone (C₁-C₄) (such as acetyl, —C(O)Et, —C(O)Pr), —S(O)Alkyl(C₁-C₄)(such as —S(O)Me, —S(O)Et), —SO₂alkyl(C₁-C₄) (such as —SO₂Me, —SO₂Et,—SO₂Pr), -thioalkyl(C₁-C₄) (such as —SMe, —SEt, —SPr, —SBu), carboxyl(such as —COOH), and/or ester (such as —C(O)OMe, —C(O)OEt, —C(O)OBu),each of which may be optionally substituted with hydrogen, F, Cl, Br,—OH, —NH₂, —NHMe, —OMe, —SMe, oxo, and/or thio-oxo.

In some embodiments, in the compound of any one of Formula Ia, FormulaIb, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, —X—R₄ is selectedfrom —CH₂Aryl.

In some embodiments, R₄ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is selected from apyridyl optionally substituted with groups independently selected fromhydrogen, deuterium, alkyl(C₁-C₄)(such as methyl, ethyl, propyl,isopropyl, butyl), alkoxy(C₁-C₄) (such as methoxy, ethoxy, isopropoxy),amino (such as —NH₂, —NHMe, —NHEt, —NHiPr, —NHBu —NMe₂, NMeEt, —NEt₂,—NEtBu, —NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as—NHC(O)Me, —NHC(O)Et, —C(O)NHMe, —C(O)NEt₂, —C(O)NiPr), —CF₃, CN, —N₃,ketone (C₁-C₄) (such as acetyl, —C(O)Et, —C(O)Pr), —S(O)Alkyl(C₁-C₄)(such as —S(O)Me, —S(O)Et), —SO₂alkyl(C₁-C₄) (such as —SO₂Me, —SO₂Et,—SO₂Pr), -thioalkyl(C₁-C₄) (such as —SMe, —SEt, —SPr, —SBu), carboxyl(such as —COOH), and/or ester (such as —C(O)OMe, —C(O)OEt, —C(O)OBu),each of which may be optionally substituted with hydrogen, F, Cl, Br,—OH, —NH₂, —NHMe, —OMe, —SMe, oxo, and/or thio-oxo.

In some embodiments, R₄ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is optionallysubstituted with groups independently selected from hydrogen, deuterium,alkyl(C₁-C₄)(such as methyl, ethyl, propyl, isopropyl, butyl),alkoxy(C₁-C₄) (such as methoxy, ethoxy, isopropoxy), amino (such as—NH₂, —NHMe, —NHEt, —NHiPr, —NHBu —NMe₂, NMeEt, —NEt₂, —NEtBu,—NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as —NHC(O)Me,—NHC(O)Et, —C(O)NHMe, —C(O)NEt₂, —C(O)NiPr), —CF₃, CN, —N₃, ketone(C₂-C₄) (such as acetyl, —C(O)Et, —C(O)Pr), —S(O)Alkyl(C₁-C₄) (such as—S(O)Me, —S(O)Et), —SO₂alkyl(C₁-C₄) (such as —SO₂Me, —SO₂Et, —SO₂Pr),-thioalkyl(C₁-C₄) (such as —SMe, —SEt, —SPr, —SBu), carboxyl (such as—COOH), and/or ester (such as —C(O)OMe, —C(O)OEt, —C(O)OBu), each ofwhich may be optionally substituted with hydrogen, F, Cl, Br, —OH, —NH₂,—NHMe, —OMe, —SMe, oxo, and/or thio-oxo.

In some embodiments, R₄ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is selected from5-6 membered carbocycles.

In some embodiments, R₄ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is selected from asmall cycloalkyl(C₃-C₆) and phenyl ring optionally optionallysubstituted with one or more groups independently selected fromdeuterium, alkyl(C₁-C₄) (such as methyl, ethyl, propyl, isopropyl, andbutyl), alkoxy(C₁-C₄) (such as methoxy, ethoxy, and isopropoxy), halogen(such as F and Cl), —CF₃, CN, and -thioalkyl(C₁-C₄) (such as, e.g.,—SMe, —SEt, —SPr, and —Sbu), wherein each alkyl, alkoxy, and thioalkylmay be optionally substituted with F, Cl, or Br.

In some embodiments, R₄ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is a phenyl ringoptionally substituted with one or more groups independently selectedfrom deuterium, alkyl(C₁-C₄) (such as methyl, ethyl, propyl, isopropyl,and butyl), alkoxy(C₁-C₄) (such as methoxy, ethoxy, and isopropoxy),halogen (such as F and Cl), —CF₃, CN, and -thioalkyl(C₁-C₄) (such as,e.g., —SMe, —SEt, —SPr, and —Sbu), wherein each alkyl, alkoxy, andthioalkyl may be optionally substituted with F, Cl, or Br.

In some embodiments, R₄ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is an aryloptionally substituted with one or more groups independently selectedfrom deuterium, alkyl(C₁-C₄) (such as methyl, ethyl, propyl, isopropyl,and butyl), alkoxy(C₁-C₄) (such as methoxy, ethoxy, and isopropoxy),halogen (such as F and Cl), —CF₃, CN, and -thioalkyl(C₁-C₄) (such as,e.g., —SMe, —SEt, —SPr, and —Sbu), wherein each alkyl, alkoxy, andthioalkyl may be optionally substituted with F, Cl, or Br.

In some embodiments, in the compound of any one of Formula Ia, FormulaIb, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, the A-B bicyclicring, is selected from

which may be optionally substituted with groups independently selectedfrom hydrogen, deuterium, —NH₂, amino (such as —NH(C₁-C₅), —N(C₁-C₅)₂,—NHPh, —NHBn, —NHpyridyl, —NHheterocycle(C₄-C₇), —NHcarbocycle(C₄-C₇)),heterocycle(C₄-C₇), carbocycle(C₄-C₇), halogen, —CN, —OH, —CF₃, sulfone,sulfoxide, alkyl(C₁-C₆), thioalkyl(C₁-C₆), Alkenyl(C₁-C₆),alkoxy(C₁-C₆), ketone(C₁-C₆), ester, urea, carboxylic acid, carbamate,amide(C₁-C₆), oxo, and thio-oxo;

-   -   D₁ is

X is selected from —CH₂— and —C(O)—;

R₄ is a phenyl ring optionally substituted with groups independentlyselected from hydrogen, deuterium, alkyl(C₁-C₄)(such as methyl, ethyl,propyl, isopropyl, butyl), alkoxy(C₁-C₄) (such as methoxy, ethoxy,isopropoxy), amino (such as —NH₂, —NHMe, —NHEt, —NHiPr, —NHBu —NMe₂,NMeEt, —NEt₂, —NEtBu, —NHC(O)NHalkyl), halogen (such as F, Cl), amide(such as —NHC(O)Me, —NHC(O)Et, —C(O)NHMe, —C(O)NEt₂, —C(O)NiPr), —CF₃,CN, —N₃, ketone (C₁-C₄) (such as acetyl, —C(O)Et, —C(O)Pr),—S(O)Alkyl(C₁-C₄) (such as —S(O)Me, —S(O)Et), —SO₂alkyl(C₁-C₄) (such as—SO₂Me, —SO₂Et, —SO₂Pr), -thioalkyl(C₁-C₄) (such as —SMe, —SEt, —SPr,—SBu), carboxyl (such as —COOH), and/or ester (such as —C(O)OMe,—C(O)OEt, —C(O)OBu), each of which may be optionally substituted withhydrogen, F, Cl, Br, —OH, —NH₂, —NHMe, —OMe, —SMe, oxo, and/or thio-oxo.

In some embodiments, in the compound of any one of Formula Ia, FormulaIb, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, the A-B bicyclicring, is selected from

which may be optionally substituted with groups independently selectedfrom hydrogen, deuterium, —NH₂, amino (such as —NH(C₁-C₅), —N(C₁-C₅)₂,—NHPh, —NHBn, —NHpyridyl, —NHheterocycle(C₄-C₇), —NHcarbocycle(C₄-C₇)),heterocycle(C₄-C₇), carbocycle(C₄-C₇), halogen, —CN, —OH, —CF₃, sulfone,sulfoxide, sulfonamide, alkyl(C₁-C₆), thioalkyl(C₁-C₆), alkenyl(C₁-C₆),alkoxy(C₁-C₆), ketone(C₁-C₆), ester, urea, carboxylic acid, carbamate,amide(C₁-C₆), oxo, and thio-oxo.

D₁ is

X is selected from —CH₂—, —CH(CH₃)—, —CH(OH)—, and —NH—;

R₄ is a phenyl ring optionally substituted with groups independentlyselected from hydrogen, deuterium, alkyl(C₁-C₄)(such as methyl, ethyl,propyl, isopropyl, butyl), alkoxy(C₁-C₄) (such as methoxy, ethoxy,isopropoxy), amino (such as —NH₂, —NHMe, —NHEt, —NHiPr, —NHBu —NMe₂,NMeEt, —NEt₂, —NEtBu, —NHC(O)NHalkyl), halogen (such as F, Cl), amide(such as —NHC(O)Me, —NHC(O)Et, —C(O)NHMe, —C(O)NEt₂, —C(O)NiPr), —CF₃,CN, —N₃, ketone (C₁-C₄) (such as acetyl, —C(O)Et, —C(O)Pr),—S(O)Alkyl(C₁-C₄) (such as —S(O)Me, —S(O)Et), —SO₂alkyl(C₁-C₄) (such as—SO₂Me, —SO₂Et, —SO₂Pr), -thioalkyl(C₁-C₄) (such as —SMe, —SEt, —SPr,—SBu), carboxyl (such as —COOH), and/or ester (such as —C(O)OMe,—C(O)OEt, —C(O)OBu), each of which may be optionally substituted withhydrogen, F, Cl, Br, —OH, —NH₂, —NHMe, —OMe, —SMe, oxo, and/or thio-oxo.

In some embodiments, —X—R₄ in the compound of any one of Formula Ia,Formula Ib, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, is —CH₂Aryl.

In some embodiments, in the compound of any one of Formula Ia, FormulaIb, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, the A-B bicyclicring is selected from

wherein Z is selected from hydrogen, deuterium, —NH₂, amino (such as—NH(C₁-C₅), —N(C₁-C₅)₂, —NHPh, —NHBn, —NHpyridyl, —NHheterocycle(C₄-C₆),—NHcarbocycle(C₄-C₅)), alkyl(C₁-C₆), thioalkyl(C₁-C₆), alkenyl(C₁-C₆),and alkoxy(C₁-C₆), carboxyl;

D₁ is

and

X is selected from —CH₂— and —CH(CHs)—; and

R₄ is a phenyl ring optionally substituted with groups independentlyselected with one or more groups independently selected from deuterium,alkyl(C₁-C₄), alkoxy(C₁-C₄), halogen, —CF₃, CN, and -thioalkyl(C₁-C₄),wherein each alkyl, alkoxy, and thioalkyl may be optionally substitutedwith F, Cl, or Br.

In some embodiments, in the compound of any one of Formula Ia, FormulaIb, Formula IIa, and Formula IIb or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, the A-B bicyclicring is selected from

wherein Z is selected from hydrogen, deuterium, —NH₂, amino (such as—NH(C₁-C₅), —N(C₁-C₅)₂, —NHPh, —NHBn, —NHpyridyl, —NHheterocycle(C₄-C₆),—NHcarbocycle(C₄-C₆)), alkyl(C₁-C₆), thioalkyl(C₁-C₆), alkenyl(C₁-C₆),and alkoxy(C₁-C₆); carboxyl;

D₁ is

X is selected from —CH₂— and —CH(CHs)—; and

R₄ is a phenyl ring optionally substituted with one or more groupsindependently selected from deuterium, alkyl(C₁-C₄) (such as methyl,ethyl, propyl, isopropyl, and butyl), alkoxy(C₁-C₄) (such as methoxy,ethoxy, and isopropoxy), halogen (such as F and Cl), —CF₃, CN, and-thioalkyl(C₁-C₄) (such as, e.g., —SMe, —SEt, —SPr, and —Sbu), whereineach alkyl, alkoxy, and thioalkyl may be optionally substituted with F,Cl, or Br.

In certain embodiments of the invention, the compound of Formula I,Formula Ia, or Formula II is selected from:

-   9-Benzyl-2-(3,5-dimethylisoxazol-4-yl)-9H-purin-6-amine;-   3-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;-   4-(3-Benzyl-3H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole;-   4-(1-Benzyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole;-   3-Benzyl-5-(3,5-dimethylisoxazol-4-yl)benzo[d]oxazol-2(3H)-one;-   1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine;-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-7-amine;-   N,1-Dibenzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine;-   1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;-   1-Benzyl-7-(3,5-dimethylisoxazol-4-yl)quinoxalin-2(1H)-one; and-   1-Benzyl-7-(3,5-dimethylisoxazol-4-yl)-3,4-dihydroquinazolin-2(1H)-one.

In certain embodiments of the invention, the compound of Formula I,Formula Ia, or Formula II is selected from:

-   9-benzyl-2-(3,5-dimethylisoxazol-4-yl)-9H-purin-6-amine;-   3-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;-   4-(3-benzyl-3H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole;-   4-(1-benzyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole;-   3-benzyl-5-(3,5-dimethylisoxazol-4-yl)benzo[d]oxazol-2(3H)-one;-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine;-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-7-amine;-   N,1-dibenzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine;-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;-   1-benzyl-7-(3,5-dimethylisoxazol-4-yl)quinoxalin-2(1H)-one;-   1-benzyl-7-(3,5-dimethylisoxazol-4-yl)-3,4-dihydroquinazolin-2(1H)-one;-   4-(1-benzyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole;-   4-(1-(cyclopropylmethyl)-2-methyl-4-nitro-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole;-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one;-   4-amino-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one;-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-amine;-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-4-nitro-1H-benzo[d]imidazol-2-amine;-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N2-ethyl-1H-benzo[d]imidazole-2,4-diamine;-   methyl    1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate;-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxamide-   4-(aminomethyl)-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one-   5-(3,5-dimethylisoxazol-4-yl)-N-phenyl-1H-pyrrolo[3,2-b]pyridin-3-amine-   6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine    4-oxide-   6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-5(4H)-one-   4-(3-benzyl-3H-imidazo[4,5-b]pyridin-5-yl)-3,5-dimethylisoxazole-   6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-1H-benzo[d]imidazol-4-amine-   6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-N-methyl-1H-benzo[d]imidazol-4-amine-   6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-N,N-dimethyl-1H-benzo[d]imidazol-4-amine-   3,5-dimethyl-4-(1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole-   4-(1-benzyl-1H-imidazo[4,5-c]pyridin-6-yl)-3,5-dimethylisoxazole-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-c]pyridine    5-oxide-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-c]pyridin-4-amine-   4-(1-benzyl-3-bromo-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde-   1-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)ethanone-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl    formate-   4-((6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)benzamide-   4-(1-benzyl-3-nitro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole-   3,5-dimethyl-4-(3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)isoxazole-   3,5-dimethyl-4-(1-(4-(trifluoromethyl)benzyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole-   4-(3-(4-chlorobenzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole-   4-(1-(4-chlorobenzyl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole-   4-(3-(4-fluorobenzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole-   4-(1-(4-fluorobenzyl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole-   3,5-dimethyl-4-(3-(pyridin-2-ylmethyl)-3H-imidazo[4,5-b]pyridin-6-yl)isoxazole-   3,5-dimethyl-4-(1-(pyridin-2-ylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole-   4-(1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole-   4-(1-(4-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-3,5-dimethylisoxazole-   4-(5-(4-fluorobenzyl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)-3,5-dimethylisoxazole-   4-(1-(4-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)-3,5-dimethylisoxazole-   6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-4-amine-   4-(1-(4-fluorobenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-6-yl)-3,5-dimethylisoxazole-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-indazol-4-amine-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-amine-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-5(4H)-one-   3-((5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)amino)benzonitrile-   4-(1-(4-fluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole-   4-(1-benzyl-2-ethoxy-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole-   4-((6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-3,5-dimethylisoxazole-   4-(1-(2,4-dichlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole-   4-(1-(4-methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole-   4-(1-(cyclopropylmethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole-   N-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)acetamide-   N-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)ethanesulfonamide-   4-(1-benzyl-4-methoxy-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole-   7-amino-3-benzyl-5-(3,5-dimethylisoxazol-4-yl)benzo[d]oxazol-2(3H)-one-   3,5-dimethyl-4-(2-methyl-1-(pyridin-3-ylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole-   3,5-dimethyl-4-(2-methyl-1-(thiophen-2-ylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole-   4-((6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)benzonitrile-   4-(1-benzyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole-   1-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)-N,N-dimethylmethanamine-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine-   3,5-dimethyl-4-(2-methyl-1-(pyridin-4-ylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole-   1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-amine-   3,5-dimethyl-4-(2-methyl-1-((5-methylthiophen-2-yl)methyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole-   4-(1-((5-chlorothiophen-2-yl)methyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole-   5-((6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)thiophene-2-carbonitrile-   6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-1H-imidazo[4,5-b]pyridine    4-oxide-   6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-1H-imidazo[4,5-b]pyridin-5-yl    acetate-   1-benzyl-6-(1,4-dimethyl-1H-pyrazol-5-yl)-2-methyl-4-nitro-1H-benzo[d]imidazole-   1-benzyl-6-(1,4-dimethyl-1H-pyrazol-5-yl)-2-methyl-1H-benzo[d]imidazol-4-amine-   4-(1-(4-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole-   4-((6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)phenol-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carbonitrile-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carbonitrile-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-morpholino-1H-benzo[d]imidazol-4-amine-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carbonitrile-   4-(1-benzyl-3-chloro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole-   4-amino-1-(4-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one-   1-(4-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one-   4-(1-benzyl-1H-pyrazolo[4,3-b]pyridin-6-yl)-3,5-dimethylisoxazole-   4-(1-(4-chlorobenzyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)-3,5-dimethylisoxazole-   1-benzyl-2-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-4-amine-   4-(1-(3,4-dichlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole-   6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1-(1-phenylethyl)-1H-benzo[d]imidazol-4-amine-   2-(azetidin-1-yl)-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine-   3,5-dimethyl-4-(1-(thiophen-3-ylmethyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)isoxazole-   N-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamide-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-amine-   1-(3,4-dichlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one-   1-(4-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-indazol-4-amine-   6-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxybenzyl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one-   4-amino-6-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxybenzyl)-1H-benzo[d]imidazol-2(3H)-one-   1-(4-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one-   6-(3,5-dimethylisoxazol-4-yl)-1-(thiophen-2-ylmethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-1H-imidazo[4,5-b]pyridin-2-amine-   3,5-dimethyl-4-(2-methyl-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole-2,4-diamine-   6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one-   N-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetamide-   6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one-   6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-2-amine-   4-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)morpholine-   4-amino-6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one-   4-(1-(cyclobutylmethyl)-2-methyl-4-nitro-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole-   4-(1-(cyclopentylmethyl)-2-methyl-4-nitro-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole-   1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one-   N-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-(ethylamino)-1H-benzo[d]imidazol-4-yl)acetamide-   N-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)acetamide-   4-(1-benzyl-4-bromo-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole-   3-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1-ethyl-1H-benzo[d]imidazol-2(3H)-one-   4-(2-(azetidin-1-yl)-1-benzyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole-   1-((5-chlorothiophen-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one-   (S)-3,5-dimethyl-4-(2-methyl-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-6-yl)isoxazole-   (R)-3,5-dimethyl-4-(2-methyl-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-6-yl)isoxazole-   6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-2-amine-   4-(1-benzyl-2-ethyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole-   4-amino-6-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxybenzyl)-1H-benzo[d]imidazol-2(3H)-one-   N-(2-(azetidin-1-yl)-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-yl)acetamide-   1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-1H-imidazo[4,5-b]pyridin-2-amine-   1-(cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-amine-   1-(cyclopentylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-amine-   6-(3,5-dimethylisoxazol-4-yl)-N2-ethyl-1-(1-phenylethyl)-1H-benzo[d]imidazole-2,4-diamine-   4-(1-benzyl-4-nitro-2-(pyrrolidin-1-yl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole-   4-(1-benzyl-2-(4-methylpiperazin-1-yl)-4-nitro-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(2-methoxyethyl)-4-nitro-1H-benzo[d]imidazol-2-amine-   4-(1-benzyl-2-cyclopropyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N2-(2-methoxyethyl)-1H-benzo[d]imidazole-2,4-diamine-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-(pyrrolidin-1-yl)-1H-benzo[d]imidazol-4-amine-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazole-amine-   1-benzyl-N6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazole-4,6-diamine-   (S)-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1-(1-phenylethyl)-1H-benzo[d]imidazol-4-amine-   (R)-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1-(1-phenylethyl)-1H-benzo[d]imidazol-4-amine-   1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-methyl-1H-imidazo[4,5-b]pyridin-2-amine-   N,1-dibenzyl-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1H-benzo[d]imidazol-2-amine-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-N-(pyridin-3-ylmethyl)-1H-benzo[d]imidazol-2-amine-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-methyl-4-nitro-1H-benzo[d]imidazol-2-amine-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-3-methyl-4-nitro-1H-benzo[d]imidazol-2(3H)-one-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N2-methyl-1H-benzo[d]imidazole-2,4-diamine-   N2,1-dibenzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazole-2,4-diamine-   N,1-dibenzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine-   1-benzyl-2-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyridine-   N-(1-benzyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazol-4-amine-   4-benzyl-6-(3,5-dimethylisoxazol-4-yl)-3,4-dihydroquinoxalin-2(1H)-one-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N2-(pyridin-3-ylmethyl)-1H-benzo[d]imidazole-2,4-diamine-   4-(1-benzyl-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole-   1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-4-nitro-1H-benzo[d]imidazol-2-amine-   1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-ethyl-1H-benzo[d]imidazole-2,4-diamine-   4-amino-1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one-   4-amino-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-4-fluoro-1H-benzo[d]imidazol-2(3H)-one-   N-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetamide-   4-(1-benzyl-2-(4-methylpiperazin-1-yl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole-   4-benzyl-6-(1-methyl-1H-pyrazol-5-yl)-3,4-dihydroquinoxalin-2(1H)-one-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(2-methoxyethyl)-1H-imidazo[4,5-b]pyridin-2-amine-   4-(1-benzyl-2-methyl-4-(methylsulfonyl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-4-ylmethyl)-1H-imidazo[4,5-b]pyridin-2-amine-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine-   1-benzyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one-   (S)-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-ol-   (R)-4-benzyl-6-(3,5-dimethylisoxazol-4-yl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one-   4-(1-benzyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyridin-2-yl)morpholine-   1-benzyl-6-(1-methyl-1H-pyrazol-5-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine-   4-amino-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazole-2(3H)-thione-   (S)-4-amino-6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one-   (R)-4-amino-6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-7-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one-   4-(1-benzyl-2,7-dimethyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole-   4-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)morpholine-   1-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)azetidin-2-one-   1-benzyl-2-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-4-amine-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-3-ylmethyl)-1H-imidazo[4,5-b]pyridin-2-amine-   4-(4-bromo-2-methyl-1-phenethyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole-   4-(4-bromo-2-methyl-1-(3-phenylpropyl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole-   4-(7-bromo-2-methyl-1-(3-phenylpropyl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole-   4-(4-bromo-2-methyl-1-(2-phenoxyethyl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole-   4-(7-bromo-2-methyl-1-(2-phenoxyethyl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole-   4-(1-(cyclohexylmethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole-   4-(1-(cyclopentylmethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole-   4-(1-(cyclobutylmethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-2-ylmethyl)-1H-imidazo[4,5-b]pyridin-2-amine-   4-(1-benzyl-2-(pyrrolidin-1-yl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole-   2-((1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)ethanol-   1-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)azetidin-3-ol-   1-benzyl-3-methyl-6-(1-methyl-1H-pyrazol-5-yl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one-   4-amino-1-benzyl-3-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-2(3H)-one-   (4-bromo-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-1-yl)(phenyl)methanone-   1-benzyl-2-methyl-6-(5-methylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine-   1-(cyclopentylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one-   1-(cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one-   N-(1-benzyl-3-methyl-6-(1-methyl-1H-pyrazol-5-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetamide-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridin-2-amine-   1-benzyl-2-methyl-6-(1-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazo[4,5-b]pyridine-   4-((1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)cyclohexanol-   4-(1-(cyclopentylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)morpholine-   4-(2-(azetidin-1-yl)-1-(cyclopentylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole-   4-(1-(cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)morpholine-   4-(2-(azetidin-1-yl)-1-(cyclobutylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole-   N1-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)-N2,N2-dimethylethane-1,2-diamine-   4-(1-benzyl-2-(piperazin-1-yl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole-   1-benzyl-N-cyclopentyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine;-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyridin-2-amine;-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine;-   3-(((1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)methyl)benzonitrile;-   (R)-6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;-   (S)-6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;-   4-(1-benzyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole;-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-methyl-1H-imidazo[4,5-b]pyridine-2-carboxamide;-   1-(cyclopentylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine;-   1-(cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine;-   N1-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)cyclohexane-1,4-diamine;-   1-benzyl-N-(cyclohexylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine;-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(3-methoxypropyl)-1H-imidazo[4,5-b]pyridin-2-amine;-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(oxetan-3-yl)-1H-imidazo[4,5-b]pyridin-2-amine;-   6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(pyrazin-2-ylmethyl)-1H-imidazo[4,5-b]pyridin-2-amine;-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyridin-2-amine;-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridin-2-amine;-   6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-N-methyl-1H-imidazo[4,5-b]pyridin-2-amine;-   1-(4-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N-methyl-1H-imidazo[4,5-b]pyridin-2-amine;-   1-benzyl-N-cyclohexyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine;-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine;-   4-(1-benzyl-2-(pyridin-3-yloxy)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole;-   1-((1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)-2-methylpropan-2-ol;-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridin-2-amine;-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(2-(piperidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridin-2-amine;-   (R)-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one;-   4-(1-benzyl-7-methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole;-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(thiazol-2-ylmethyl)-1H-imidazo[4,5-b]pyridin-2-amine;-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazole-2-carboximidamide;-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazole-2-carboxamide;-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methylpiperidin-4-yl)methyl)-1H-imidazo[4,5-b]pyridin-2-amine;-   1-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)azetidin-3-ol;-   4-(1-benzyl-2-(pyridin-4-yloxy)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole;-   1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-3-yl)-1H-benzo[d]imidazol-2-amine;    and-   3-(1-benzyl-1H-benzo[d]imidazol-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one;

or a stereoisomer, tautomer, salt, or hydrate thereof.

Another aspect of the invention provides a method for inhibition of BETprotein function by binding to bromodomains, and their use in thetreatment and prevention of diseases and conditions in a mammal (e.g., ahuman) comprising administering a therapeutically effective amount of acompound of Formula I, Formula Ia, and/or Formula II.

In one embodiment, because of potent effects of BET inhibitors in vitroon IL-6 and IL-17 transcription, BET inhibitor compounds of Formula I,Formula Ia, and/or Formula II may be used as therapeutics forinflammatory disorders in which IL-6 and/or IL-17 have been implicatedin disease. The following autoimmune diseases are amenable totherapeutic use of BET inhibition by administration of a compound ofFormula I, Formula Ia, and/or Formula II or stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate of Formula I, Formula Ia,and/or Formula II because of a prominent role of IL-6 and/or IL-17:Acute Disseminated Encephalomyelitis (Ishizu, T., et al., “CSF cytokineand chemokine profiles in acute disseminated encephalomyelitis,” JNeuroimmunol 175(1-2): 52-8 (2006)), Agammaglobulinemia(Gonzalez-Serrano, M. E., et al., “Increased Pro-inflammatory CytokineProduction After Lipopolysaccharide Stimulation in Patients withX-linked Agammaglobulinemia,” J Clin Immunol 32(5):967-74 (2012)),Allergic Disease (McKinley, L., et al., “TH17 cells mediatesteroid-resistant airway inflammation and airway hyperresponsiveness inmice,” J Immunol 181(6):4089-97 (2008)), Ankylosing spondylitis (Taylan,A., et al., “Evaluation of the T helper 17 axis in ankylosingspondylitis,” Rheumatol Int 32(8):2511-5 (2012)), Anti-GBM/Anti-TBMnephritis (Ito, Y., et al., “Pathogenic significance of interleukin-6 ina patient with antiglomerular basement membrane antibody-inducedglomerulonephritis with multinucleated giant cells,” Am J Kidney Dis26(1):72-9 (1995)), Anti-phospholipid syndrome (Soltesz, P., et al.,“Immunological features of primary anti-phospholipid syndrome inconnection with endothelial dysfunction,” Rheumatology (Oxford)47(11):1628-34 (2008)), Autoimmune aplastic anemia (Gu, Y., et al.,“Interleukin (IL)-17 promotes macrophages to produce IL-8, IL-6 andtumour necrosis factor-alpha in aplastic anaemia,” Br J Haematol142(1):109-14 (2008)), Autoimmune hepatitis (Zhao, L., et al.,“Interleukin-17 contributes to the pathogenesis of autoimmune hepatitisthrough inducing hepatic interleukin-6 expression,” PLoS One 6(4):e18909(2011)), Autoimmune inner ear disease (Gloddek, B., et al.,“Pharmacological influence on inner ear endothelial cells in relation tothe pathogenesis of sensorineural hearing loss,” Adv Otorhinolaryngol59:75-83 (2002)), Autoimmune myocarditis (Yamashita, T., et al.,“IL-6-mediated Th17 differentiation through RORgammat is essential forthe initiation of experimental autoimmune myocarditis,” Cardiovasc Res91(4):640-8 (2011)), Autoimmune pancreatitis (Ni, J., et al.,“Involvement of Interleukin-17A in Pancreatic Damage in Rat ExperimentalAcute Necrotizing Pancreatitis,” Inflammation (2012)), Autoimmuneretinopathy (Hohki, S., et al., “Blockade of interleukin-6 signalingsuppresses experimental autoimmune uveoretinitis by the inhibition ofinflammatory Th17 responses,” Exp Eye Res 91(2):162-70 (2010)),Autoimmune thrombocytopenic purpura (Ma, D., et al., “Profile of Th17cytokines (IL-17, TGF-beta, IL-6) and Th1 cytokine (IFN-gamma) inpatients with immune thrombocytopenic purpura,” Ann Hematol87(11):899-904 (2008)), Behcet's Disease (Yoshimura, T., et al.,“Involvement of Th17 cells and the effect of anti-IL-6 therapy inautoimmune uveitis,” Rheumatology (Oxford) 48(4):347-54 (2009)), Bullouspemphigoid (D'Auria, L., P. et al., “Cytokines and bullous pemphigoid,”Eur Cytokine Netw 10(2):123-34 (1999)), Castleman's Disease (El-Osta, H.E. and R. Kurzrock, “Castleman's disease: from basic mechanisms tomolecular therapeutics,” Oncologist 16(4):497-511 (2011)), CeliacDisease (Lahdenpera, A. I., et al., “Up-regulation of small intestinalinterleukin-17 immunity in untreated coeliac disease but not inpotential coeliac disease or in type 1 diabetes,” Clin Exp Immunol167(2):226-34 (2012)), Churg-Strauss syndrome (Fujioka, A., et al., “Theanalysis of mRNA expression of cytokines from skin lesions inChurg-Strauss syndrome,” J Dermatol 25(3):171-7 (1998)), Crohn's Disease(Holtta, V., et al., “IL-23/IL-17 immunity as a hallmark of Crohn'sdisease,” Inflamm Bowel Dis 14(9):1175-84 (2008)), Cogan's syndrome(Shibuya, M., et al., “Successful treatment with tocilizumab in a caseof Cogan's syndrome complicated with aortitis,” Mod Rheumatol (2012)),Dry eye syndrome (De Paiva, C. S., et al., “IL-17 disrupts cornealbarrier following desiccating stress,” Mucosal Immunol 2(3):243-53(2009)), Essential mixed cryoglobulinemia (Antonelli, A., et al., “Serumlevels of proinflammatory cytokines interleukin-1beta, interleukin-6,and tumor necrosis factor alpha in mixed cryoglobulinemia,” ArthritisRheum 60(12):3841-7 (2009)), Dermatomyositis (Chevrel, G., et al.,“Interleukin-17 increases the effects of IL-1 beta on muscle cells:arguments for the role of T cells in the pathogenesis of myositis,” JNeuroimmunol 137(1-2):125-33 (2003)), Devic's Disease (Linhares, U. C.,et al., “The Ex Vivo Production of IL-6 and IL-21 by CD4(+) T Cells isDirectly Associated with Neurological Disability in Neuromyelitis OpticaPatients,” J Clin Immunol (2012)), Encephalitis (Kyburz, D. and M. Corr,“Th17 cells generated in the absence of TGF-beta induce experimentalallergic encephalitis upon adoptive transfer,” Expert Rev Clin Immunol7(3):283-5 (2011)), Eosinophlic esophagitis (Dias, P. M. and G.Banerjee, “The Role of Th17/IL-17 on Eosinophilic Inflammation,” JAutoimmun (2012)), Eosinophilic fasciitis (Dias, P. M. and G. Banerjee,“The Role of Th17/IL-17 on Eosinophilic Inflammation,” J Autoimmun(2012)), Erythema nodosum (Kahawita, I. P. and D. N. Lockwood, “Towardsunderstanding the pathology of erythema nodosum leprosum,” Trans R SocTrop Med Hyg 102(4):329-37 (2008)), Giant cell arteritis (Deng, J., etal., “Th17 and Th1 T-cell responses in giant cell arteritis,”Circulation 121(7):906-15 (2010)), Glomerulonephritis (Ooi, J. D., etal., “Review: T helper 17 cells: their role in glomerulonephritis,”Nephrology (Carlton) 15(5):513-21 (2010)), Goodpasture's syndrome (Ito,Y., et al., “Pathogenic significance of interleukin-6 in a patient withantiglomerular basement membrane antibody-induced glomerulonephritiswith multinucleated giant cells,” Am J Kidney Dis 26(1):72-9 (1995)),Granulomatosis with Polyangiitis (Wegener's) (Nakahama, H., et al.,“Distinct responses of interleukin-6 and other laboratory parameters totreatment in a patient with Wegener's granulomatosis,” Intern Med32(2):189-92 (1993)), Graves' Disease (Kim, S. E., et al., “Increasedserum interleukin-17 in Graves' ophthalmopathy,” Graefes Arch Clin ExpOphthalmol 250(10):1521-6 (2012)), Guillain-Barre syndrome (Lu, M. O.and J. Zhu, “The role of cytokines in Guillain-Barre syndrome,” J Neurol258(4):533-48 (2011)), Hashimoto's thyroiditis (Figueroa-Vega, N., etal., “Increased circulating pro-inflammatory cytokines and Th17lymphocytes in Hashimoto's thyroiditis,”J Clin Endocrinal Metab95(2):953-62 (2009)), Hemolytic anemia (Xu, L., et al., “Critical roleof Th17 cells in development of autoimmune hemolytic anemia,” ExpHematol (2012)), Henoch-Schonlein purpura (Jen, H. Y., et al.,“Increased serum interleukin-17 and peripheral Th17 cells in childrenwith acute Henoch-Schonlein purpura,” Pediatr Allergy Immunol22(8):862-8 (2011)), IgA nephropathy (Lin, F. J., et al., “Imbalance ofregulatory T cells to Th17 cells in IgA nephropathy,” Scand J Clin LabInvest 72(3):221-9 (2012)), Inclusion body myositis (Baron, P., et al.,“Production of IL-6 by human myoblasts stimulated with Abeta: relevancein the pathogenesis of IBM,” Neurology 57(9):1561-5 (2001)), Type Idiabetes (Belkina, A. C. and G. V. Denis, “BET domain co-regulators inobesity, inflammation and cancer,” Nat Rev Cancer 12(7):465-77 (2012)),Interstitial cystitis (Lamale, L. M., et al., “Interleukin-6, histamine,and methylhistamine as diagnostic markers for interstitial cystitis,”Urology 68(4):702-6 (2006)), Kawasaki's Disease (Jia, S., et al., “The Thelper type 17/regulatory T cell imbalance in patients with acuteKawasaki disease,” Clin Exp Immunol 162(1):131-7 (2010)),Leukocytoclastic vasculitis (Min, C. K., et al., “Cutaneous leucoclasticvasculitis (LV) following bortezomib therapy in a myeloma patient;association with pro-inflammatory cytokines,” Eur J Haematol 76(3):265-8(2006)), Lichen planus (Rhodus, N. L., et al., “Proinflammatory cytokinelevels in saliva before and after treatment of (erosive) oral lichenplanus with dexamethasone,” Oral Dis 12(2):112-6 (2006)), Lupus (SLE)(Mok, M. Y., et al., “The relation of interleukin 17 (IL-17) and IL-23to Th1/Th2 cytokines and disease activity in systemic lupuserythematosus,” J Rheumatol 37(10):2046-52 (2010)), Microscopicpolyangitis (Muller Kobold, A. C., et al., “In vitro up-regulation ofE-selectin and induction of interleukin-6 in endothelial cells byautoantibodies in Wegener's granulomatosis and microscopicpolyangiitis,” Clin Exp Rheumatol 17(4):433-40 (1999)), Multiplesclerosis (Jadidi-Niaragh, F. and Mirshafiey A., “Th17 cell, the newplayer of neuroinflammatory process in multiple sclerosis,” Scand JImmunol 74(1):1-13 (2011)), Myasthenia gravis (Aricha, R., et al.,“Blocking of IL-6 suppresses experimental autoimmune myasthenia gravis,”J Autoimmun 36(2):135-41 (2011)), myositis (Chevrel, G., et al.,“Interleukin-17 increases the effects of IL-1 beta on muscle cells:arguments for the role of T cells in the pathogenesis of myositis,” JNeuroimmunol 137(1-2):125-33 (2003)), Optic neuritis (Icoz, S., et al.,“Enhanced IL-6 production in aquaporin-4 antibody positive neuromyelitisoptica patients,” Int J Neurosci 120(1):71-5 (2010)), Pemphigus(Lopez-Robles, E., et al., “TNF alpha and IL-6 are mediators in theblistering process of pemphigus,” Int J Dermatol 40(3):185-8 (2001)),POEMS syndrome (Kallen, K. J., et al., “New developments in IL-6dependent biology and therapy: where do we stand and what are theoptions?” Expert Opin Investig Drugs 8(9):1327-49 (1999)), Polyarteritisnodosa (Kawakami, T., et al., “Serum levels of interleukin-6 in patientswith cutaneous polyarteritis nodosa,” Acta Derm Venereol 92(3):322-3(2012)), Primary biliary cirrhosis (Harada, K., et al., “Periductalinterleukin-17 production in association with biliary innate immunitycontributes to the pathogenesis of cholangiopathy in primary biliarycirrhosis,” Clin Exp Immunol 157(2):261-70 (2009)), Psoriasis(Fujishima, S., et al., “Involvement of IL-17F via the induction of IL-6in psoriasis,” Arch Dermatol Res 302(7):499-505 (2010)), Psoriaticarthritis (Raychaudhuri, S. P., et al., IL-17 receptor and itsfunctional significance in psoriatic arthritis, ”Mol Cell Biochem359(1-2):419-29 (2012)), Pyoderma gangrenosum (Kawakami, T., et al.,“Reduction of interleukin-6, interleukin-8, andanti-phosphatidylserine-prothrombin complex antibody by granulocyte andmonocyte adsorption apheresis in a patient with pyoderma gangrenosum andulcerative colitis,” Am J Gastroenterol 104(9):2363-4 (2009)), Relapsingpolychondritis (Kawai, M., et al., “Sustained response to tocilizumab,anti-interleukin-6 receptor antibody, in two patients with refractoryrelapsing polychondritis,” Rheumatology (Oxford) 48(3):318-9 (2009)),Rheumatoid arthritis (Ash, Z. and P. Emery, “The role of tocilizumab inthe management of rheumatoid arthritis,” Expert Opin Biol Ther,12(9):1277-89 (2012)), Sarcoidosis (Belli, F., et al., “Cytokines assayin peripheral blood and bronchoalveolar lavage in the diagnosis andstaging of pulmonary granulomatous diseases,” Int J ImmunopatholPharmacol 13(2):61-67 (2000)), Scleroderma (Radstake, T. R., et al.,“The pronounced Th17 profile in systemic sclerosis (SSc) together withintracellular expression of TGFbeta and IFNgamma distinguishes SScphenotypes,” PLoS One, 4(6): e5903 (2009)), Sjogren's syndrome(Katsifis, G. E., et al., “Systemic and local interleukin-17 and linkedcytokines associated with Sjogren's syndrome immunopathogenesis,” Am JPathol 175(3):1167-77 (2009)), Takayasu's arteritis (Sun, Y., et al.,“MMP-9 and IL-6 are potential biomarkers for disease activity inTakayasu's arteritis,” Int J Cardiol 156(2):236-8 (2012)), Transversemyelitis (Graber, J. J., et al., “Interleukin-17 in transverse myelitisand multiple sclerosis,” J Neuroimmunol 196(1-2):124-32 (2008)),Ulcerative colitis (Mudter, J. and M. F. Neurath, “11-6 signaling ininflammatory bowel disease: pathophysiological role and clinicalrelevance,” Inflamm Bowel Dis 13(8):1016-23 (2007)), Uveitis (Haruta,H., et al., “Blockade of interleukin-6 signaling suppresses not onlyth17 but also interphotoreceptor retinoid binding protein-specific Th1by promoting regulatory T cells in experimental autoimmuneuveoretinitis,” Invest Ophthalmol Vis Sci 52(6):3264-71 (2011)), andVitiligo (Bassiouny, D. A. and O. Shaker, “Role of interleukin-17 in thepathogenesis of vitiligo,” Clin Exp Dermatol 36(3):292-7 115. (2011)).Thus, the invention includes compounds of Formula I, Formula Ia, and/orFormula II, stereoisomers, tautomers, pharmaceutically acceptable salts,or hydrates thereof; pharmaceutical compositions comprising one or moreof those compounds; and methods of using those compounds or compositionsfor treating these diseases.

Acute and chronic (non-autoimmune) inflammatory diseases characterizedby increased expression of pro-inflammatory cytokines, including IL-6,MCP-1, and IL-17, would also be amenable to therapeutic BET inhibition.These include, but are not limited to, sinusitis (Bradley, D. T. and S.E. Kountakis, “Role of interleukins and transforming growth factor-betain chronic rhinosinusitis and nasal polyposis,” Laryngoscope115(4):684-6 (2005)), pneumonitis (Besnard, A. G., et al.,“Inflammasome-IL-1-Th17 response in allergic lung inflammation” J MolCell Biol 4(1):3-10 (2012)), osteomyelitis (Yoshii, T., et al., “Locallevels of interleukin-1beta, -4, -6 and tumor necrosis factor alpha inan experimental model of murine osteomyelitis due to Staphylococcusaureus,” Cytokine 19(2):59-65 2002), gastritis (Bayraktaroglu, T., etal., “Serum levels of tumor necrosis factor-alpha, interleukin-6 andinterleukin-8 are not increased in dyspeptic patients with Helicobacterpylori-associated gastritis,” Mediators Inflamm 13(1):25-8 (2004)),enteritis (Mitsuyama, K., et al., “STAT3 activation via interleukin 6trans-signalling contributes to ileitis in SAMP1/Yit mice,” Gut55(9):1263-9. (2006)), gingivitis (Johnson, R. B., et al.,“Interleukin-11 and IL-17 and the pathogenesis of periodontal disease,”J Periodontol 75(1):37-43 (2004)), appendicitis (Latifi, S. Q., et al.,“Persistent elevation of serum interleukin-6 in intraabdominal sepsisidentifies those with prolonged length of stay,” J Pediatr Surg39(10):1548-52 (2004)), irritable bowel syndrome (Ortiz-Lucas, M., etal., “Irritable bowel syndrome immune hypothesis. Part two: the role ofcytokines,” Rev Esp Enferm Dig 102(12):711-7 (2010)), tissue graftrejection (Kappel, L. W., et al., “IL-17 contributes to CD4-mediatedgraft-versus-host disease,” Blood 113(4):945-52 (2009)), chronicobstructive pulmonary disease (COPD) (Traves, S. L. and L. E. Donnelly,“Th17 cells in airway diseases,” Curr Mol Med 8(5):416-26 (2008)),septic shock (toxic shock syndrome, SIRS, bacterial sepsis, etc)(Nicodeme, E., et al., “Suppression of inflammation by a synthetichistone mimic,” Nature 468(7327):1119-23 (2010)), osteoarthritis (Chen,L., et al., “IL-17RA aptamer-mediated repression of IL-6 inhibitssynovium inflammation in a murine model of osteoarthritis,”Osteoarthritis Cartilage 19(6):711-8 (2011)), acute gout (Urano, W., etal., “The inflammatory process in the mechanism of decreased serum uricacid concentrations during acute gouty arthritis,” J Rheumatol29(9):1950-3 (2002)), acute lung injury (Traves, S. L. and L. E.Donnelly, “Th17 cells in airway diseases,” Curr Mol Med 8(5):416-26(2008)), acute renal failure (Simmons, E. M., et al., “Plasma cytokinelevels predict mortality in patients with acute renal failure,” KidneyInt 65(4):1357-65 (2004)), burns (Paquet, P. and G. E. Pierard,“Interleukin-6 and the skin,” Int Arch Allergy Immunol 109(4):308-17(1996)), Herxheimer reaction (Kaplanski, G., et al., “Jarisch-Herxheimerreaction complicating the treatment of chronic Q fever endocarditis:elevated TNFalpha and IL-6 serum levels,” J Infect 37(1):83-4 (1998)),and SIRS associated with viral infections (Belkina, A. C. and G. V.Denis, “BET domain co-regulators in obesity, inflammation and cancer,”Nat Rev Cancer 12(7):465-77 (2012)). Thus, the invention includescompounds of Formula I, Formula Ia, and/or Formula II, stereoisomers,tautomers, pharmaceutically acceptable salts, or hydrates thereof;pharmaceutical compositions comprising one or more of those compounds;and methods of using those compounds or compositions for treating thesediseases.

In one embodiment, BET inhibitor compounds of Formula I, Formula Ia,and/or Formula II, stereoisomers, tautomers, pharmaceutically acceptablesalts, or hydrates thereof, or compositions comprising one or more ofthose compounds may be used for treating rheumatoid arthritis (RA) andmultiple sclerosis (MS). Strong proprietary data exist for the utilityof BET inhibitors in preclinical models of RA and MS. R. Jahagirdar, S.M. et al., “An Orally Bioavailable Small Molecule RVX-297 SignificantlyDecreases Disease in a Mouse Model of Multiple Sclerosis,” WorldCongress of Inflammation, Paris, France (2011). Both RA and MS arecharacterized by a dysregulation of the IL-6 and IL-17 inflammatorypathways (Kimura, A. and T. Kishimoto, “IL-6: regulator of Treg/Th17balance,” Eur J Immunol 40(7):1830-5 (2010)) and thus would beespecially sensitive to BET inhibition. In another embodiment, BETinhibitor compounds of Formula I, Formula Ia, and/or Formula II may beused for treating sepsis and associated afflictions. BET inhibition hasbeen shown to inhibit development of sepsis, in part, by inhibiting IL-6expression, in preclinical models in both published (Nicodeme, E., etal., “Suppression of inflammation by a synthetic histone mimic,” Nature468(7327):1119-23 (2010)) and proprietary data.

In one embodiment, BET inhibitor compounds of Formula I, Formula Ia,and/or Formula II, stereoisomers, tautomers, pharmaceutically acceptablesalts, or hydrates thereof, or compositions comprising one or more ofthose compounds may be used to treat cancer. Cancers that have anoverexpression, translocation, amplification, or rearrangement c-myc orother myc family oncoproteins (MYCN, L-myc) are particularly sensitiveto BET inhibition. Delmore, J. E., et al., “BET bromodomain inhibitionas a therapeutic strategy to target c-Myc,” Cell 146(6):904-17 (2010);Mertz, J. A., et al., “Targeting MYC dependence in cancer by inhibitingBET bromodomains,” Proc Natl Acad Sci USA 108(40):16669-74 (2011). Thesecancers include, but are not limited to, B-acute lymphocytic leukemia,Burkitt's lymphoma, Diffuse large cell lymphoma, Multiple myeloma,Primary plasma cell leukemia, Atypical carcinoid lung cancer, Bladdercancer, Breast cancer, Cervix cancer, Colon cancer, Gastric cancer,Glioblastoma, Hepatocellular carcinoma, Large cell neuroendocrinecarcinoma, Medulloblastoma, Melanoma, nodular, Melanoma, superficialspreading, Neuroblastoma, esophageal squamous cell carcinoma,Osteosarcoma, Ovarian cancer, Prostate cancer, Renal clear cellcarcinoma, Retinoblastoma, Rhabdomyosarcoma, and Small cell lungcarcinoma. Vita, M. and M. Henriksson, “The Myc oncoprotein as atherapeutic target for human cancer,” Semin Cancer Biol 16(4):318-30(2006).

In one embodiment, BET inhibitor compounds of Formula I, Formula Ia,and/or Formula II, stereoisomers, tautomers, pharmaceutically acceptablesalts, or hydrates thereof, or compositions comprising one or more ofthose compounds may be used to treat cancers that result from anaberrant regulation (overexpression, translocation, etc) of BETproteins. These include, but are not limited to, NUT midline carcinoma(Brd3 or Brd4 translocation to nutlin 1 gene) (French, C. A., “NUTmidline carcinoma,” Cancer Genet Cytogenet 203(1):16-20 (2010)), B-celllymphoma (Brd2 overexpression) (Greenwald, R. J., et al., “E mu-BRD2transgenic mice develop B-cell lymphoma and leukemia,”. Blood103(4):1475-84 (2004)), non-small cell lung cancer (BrdT overexpression)(Grunwald, C., et al., “Expression of multiple epigenetically regulatedcancer/germline genes in nonsmall cell lung cancer,” Int J Cancer118(10):2522-8 (2006)), esophageal cancer and head and neck squamouscell carcinoma (BrdT overexpression) (Scanlan, M. J., et al.,“Expression of cancer-testis antigens in lung cancer: definition ofbromodomain testis-specific gene (BRDT) as a new CT gene, CT9,” CancerLett 150(2):55-64 (2000)), and colon cancer (Brd4) (Rodriguez, R. M., etal., “Aberrant epigenetic regulation of bromodomain BRD4 in human coloncancer,” J Mol Med (Berl) 90(5):587-95 (2012)).

In one embodiment, because BET inhibitors decrease Brd-dependentrecruitment of pTEFb to genes involved in cell proliferation, BETinhibitor compounds of Formula I, Formula Ia, and/or Formula II,stereoisomers, tautomers, pharmaceutically acceptable salts, or hydratesthereof, or compositions comprising one or more of those compounds maybe used to treat cancers that rely on pTEFb (Cdk9/cyclin T) and BETproteins to regulate oncogenes. These cancers include, but are notlimited to, chronic lymphocytic leukemia and multiple myeloma (Tong, W.G., et al., “Phase I and pharmacologic study of SNS-032, a potent andselective Cdk2, 7, and 9 inhibitor, in patients with advanced chroniclymphocytic leukemia and multiple myeloma,” J Clin Oncol 28(18):3015-22(2010)), follicular lymphoma, diffuse large B cell lymphoma withgerminal center phenotype, Burkitt's lymphoma, Flodgkin's lymphoma,follicular lymphomas and activated, anaplastic large cell lymphoma(Bellan, C., et al., “CDK9/CYCLIN T1 expression during normal lymphoiddifferentiation and malignant transformation,” J Pathol 203(4):946-52(2004)), neuroblastoma and primary neuroectodermal tumor (De Falco, G.,et al., “Cdk9 regulates neural differentiation and its expressioncorrelates with the differentiation grade of neuroblastoma and PNETtumors,” Cancer Biol Ther 4(3):277-81 (2005)), rhabdomyosarcoma (Simone,C. and A. Giordano, “Abrogation of signal-dependent activation of thecdk9/cyclin T2a complex in human RD rhabdomyosarcoma cells,” Cell DeathDiffer 14(1):192-5 (2007)), prostate cancer (Lee, D. K., et al.,“Androgen receptor interacts with the positive elongation factor P-TEFband enhances the efficiency of transcriptional elongation,” J Biol Chem276(13):9978-84 (2001)), and breast cancer (Bartholomeeusen, K., et al.,“BET bromodomain inhibition activates transcription via a transientrelease of P-TEFb from 7SK snRNP,” J Biol Chem (2012)).

In one embodiment, BET inhibitor compounds of Formula I, Formula Ia,and/or Formula II, stereoisomers, tautomers, pharmaceutically acceptablesalts, or hydrates thereof, or compositions comprising one or more ofthose compounds may be used to treat cancers in which BET-responsivegenes, such as CDK6, Bcl2, TYRO3, MYB, and hTERT are up-regulated.Dawson, M. A., et al., “Inhibition of BET recruitment to chromatin as aneffective treatment for MLL-fusion leukaemia,” Nature 478(7370):529-33(2011); Delmore, J. E., et al., “BET bromodomain inhibition as atherapeutic strategy to target c-Myc,” Cell 146(6):904-17 (2010). Thesecancers include, but are not limited to, pancreatic cancer, breastcancer, colon cancer, glioblastoma, adenoid cystic carcinoma, T-cellprolymphocytic leukemia, malignant glioma, bladder cancer,medulloblastoma, thyroid cancer, melanoma, multiple myeloma, Barret'sadenocarcinoma, hepatoma, prostate cancer, pro-myelocytic leukemia,chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-celllymphoma, small cell lung cancer, and renal carcinoma. Ruden, M. and N.Puri, “Novel anticancer therapeutics targeting telomerase,” Cancer TreatRev (2012); Kelly, P. N. and A. Strasser, “The role of Bcl-2 and itspro-survival relatives in tumourigenesis and cancer therapy” Cell DeathDiffer 18(9):1414-24 (2011); Uchida, T., et al., “Antitumor effect ofbcl-2 antisense phosphorothioate oligodeoxynucleotides on humanrenal-cell carcinoma cells in vitro and in mice,” Mol Urol 5(2):71-8(2001).

Published and proprietary data have shown direct effects of BETinhibition on cell proliferation in various cancers. In one embodiment,BET inhibitor compounds of Formula I, Formula Ia, and/or Formula II,stereoisomers, tautomers, pharmaceutically acceptable salts, or hydratesthereof, or compositions comprising one or more of those compounds maybe used to treat cancers for which exist published and, for some,proprietary, in vivo and/or in vitro data showing a direct effect of BETinhibition on cell proliferation. These cancers include NMC (NUT-midlinecarcinoma), acute myeloid leukemia (AML), acute B lymphoblastic leukemia(B-ALL), Burkitt's Lymphoma, B-cell Lymphoma, Melanoma, mixed lineageleukemia, multiple myeloma, pro-myelocytic leukemia (PML), andnon-Hodgkin's lymphoma. Filippakopoulos, P., et al., “Selectiveinhibition of BET bromodomains,” Nature 468(7327):1067-73 (2010);Dawson, M. A., et al., “Inhibition of BET recruitment to chromatin as aneffective treatment for MLL-fusion leukaemia,” Nature 478(7370):529-33(2011); Zuber, J., et al., “RNAi screen identifies Brd4 as a therapeutictarget in acute myeloid leukaemia,” Nature 478(7370):524-8 (2011);Miguel F. Segura, et al, “BRD4 is a novel therapeutic target inmelanoma,” Cancer Research. 72(8):Supplement 1 (2012). The compounds ofthe invention have a demonstrated BET inhibition effect on cellproliferation in vitro for the following cancers: Neuroblastoma,Medulloblastoma, lung carcinoma (NSCLC, SCLC), and colon carcinoma.

In one embodiment, because of potential synergy or additive effectsbetween BET inhibitors and other cancer therapy, BET inhibitor compoundsof Formula I, Formula Ia, and/or Formula II, stereoisomers, tautomers,pharmaceutically acceptable salts, or hydrates thereof, or compositionscomprising one or more of those compounds may be combined with othertherapies, chemotherapeutic agents, or anti-proliferative agents totreat human cancer and other proliferative disorders. The list oftherapeutic agents which can be combined with BET inhibitors in cancertreatment includes, but is not limited to, ABT-737, Azacitidine(Vidaza®), AZD1152 (Barasertib), AZD2281 (Olaparib), AZD6244(Selumetinib), BEZ235, Bleomycin Sulfate, Bortezomib (Velcade®),Busulfan (Myleran®), Camptothecin, Cisplatin, Cyclophosphamide(Clafen®), CVT387, Cytarabine (AraC), Dacarbazine, DAPT (GSI-IX),Decitabine, Dexamethasone, Doxorubicin (Adriamycin®), Etoposide,Everolimus (RAD00I), Flavopiridol (Alvocidib), Ganetespib (STA-9090),Gefitinib (Iressa®), Idarubicin, Ifosfamide (Mitoxana), IFNa2a (Roferon®A), Melphalan (Alkeran®), Methazolastone (temozolomide), Metformin,Mitoxantrone (Novantrone®), Paclitaxel, Phenformin, PKC412(Midostaurin), PLX4032 (Vemurafenib), Pomalidomide (CC-4047), Prednisone(Deltasone®), Rapamycin, Revlimid® (Lenalidomide), Ruxolitinib(INCB018424), Sorafenib (Nexavar®), SU11248 (Sunitinib), SU11274,Vinblastine, Vincristine (Oncovin®), Vinorelbine (Navelbine®),Vorinostat (SAHA), and WP1130 (Degrasyn).

In one embodiment, BET inhibitor compounds of Formula I, Formula Ia,and/or Formula II, stereoisomers, tautomers, pharmaceutically acceptablesalts, or hydrates thereof, or compositions comprising one or more ofthose compounds may be used to treat benign proliferative and fibroticdisorders, including, but not limited to, benign soft tissue tumors,bone tumors, brain and spinal tumors, eyelid and orbital tumors,granuloma, lipoma, meningioma, multiple endocrine neoplasia, nasalpolyps, pituitary tumors, prolactinoma, pseudotumor cerebri, seborrheickeratoses, stomach polyps, thyroid nodules, cystic neoplasms of thepancreas, hemangiomas, vocal cord nodules, polyps, and cysts, Castlemandisease, chronic pilonidal disease, dermatofibroma, pilar cyst, pyogenicgranuloma, juvenile polyposis syndrome, idiopathic pulmonary fibrosis,renal fibrosis, post-operative stricture, keloid formation, scleroderma,and cardiac fibrosis. Tang, X et al., “Assessment of Brd4 Inhibition inIdiopathic Pulmonary Fibrosis Lung Fibroblasts and in Vivo Models ofLung Fibrosis,”.Am J Pathology in press (2013).

In one embodiment, because of their ability to up-regulate ApoA-1transcription and protein expression (Mirguet, O., et al., “From ApoA1upregulation to BET family bromodomain inhibition: discovery ofI-BET151,” Bioorg Med Chem Lett 22(8):2963-7 (2012); Chung, C. W., etal., “Discovery and characterization of small molecule inhibitors of theBET family bromodomains,” J Med Chem 54(11):3827-38 (2011)), BETinhibitor compounds of Formula I, Formula Ia, and/or Formula II,stereoisomers, tautomers, pharmaceutically acceptable salts, or hydratesthereof, or compositions comprising one or more of those compounds maybe used to treat cardiovascular diseases that are generally associatedwith including dyslipidemia, atherosclerosis, hypercholesterolemia, andmetabolic syndrome (Belkina, A. C. and G. V. Denis, “BET domainco-regulators in obesity, inflammation and cancer,” Nat Rev Cancer12(7):465-77 (2012); Denis, G. V., “Bromodomain coactivators in cancer,obesity, type 2 diabetes, and inflammation,” Discov Med 10(55):489-99(2010)). In another embodiment, BET inhibitor compounds of Formula I,Formula Ia, and/or Formula II may be used to treat non-cardiovasculardisease characterized by deficits in ApoA-1, including Alzheimer'sdisease. Elliott, D. A., et al., “Apolipoproteins in the brain:implications for neurological and psychiatric disorders,” Clin Lipidol51(4):555-573 (2010).

In one embodiment, BET inhibitor compounds of Formula I, Formula Ia,and/or Formula II, stereoisomers, tautomers, pharmaceutically acceptablesalts, or hydrates thereof, or compositions comprising one or more ofthose compounds may be used in patients with insulin resistance and typeII diabetes. Belkina, A. C. and G. V. Denis, “BET domain co-regulatorsin obesity, inflammation and cancer,” Nat Rev Cancer 12(7):465-77(2012); Denis, G. V., “Bromodomain coactivators in cancer, obesity, type2 diabetes, and inflammation,” Discov Med 10(55):489-99 (2010); Wang,F., et al., “Brd2 disruption in mice causes severe obesity without Type2 diabetes,” Biochem J 425(1):71-83 (2010); Denis, G. V., et al, “Anemerging role for bromodomain-containing proteins in chromatinregulation and transcriptional control of adipogenesis,” FEBS Lett584(15):3260-8 (2010). The anti-inflammatory effects of BET inhibitionwould have additional value in decreasing inflammation associated withdiabetes and metabolic disease. Alexandraki, K., et al., “Inflammatoryprocess in type 2 diabetes: The role of cytokines,” Ann N Y Acad Sci1084:89-117 (2006).

In one embodiment, because of their ability to down-regulate viralpromoters, BET inhibitor compounds of Formula I, Formula Ia, and/orFormula II, stereoisomers, tautomers, pharmaceutically acceptable salts,or hydrates thereof, or compositions comprising one or more of thosecompounds may be used as therapeutics for cancers that are associatedwith viruses including Epstein-Barr Virus (EBV), hepatitis virus (HBV,HCV), Kaposi's sarcoma associated virus (KSHV), human papilloma virus(HPV), Merkel cell polyomavirus, and human cytomegalovirus (CMV).Gagnon, D., et al., “Proteasomal degradation of the papillomavirus E2protein is inhibited by overexpression of bromodomain-containing protein4,” J Virol 83(9):4127-39 (2009); You, J., et al., “Kaposi'ssarcoma-associated herpesvirus latency-associated nuclear antigeninteracts with bromodomain protein Brd4 on host mitotic chromosomes,”JVirol 80(18):8909-19 (2006); Palermo, R. D., et al., “RNA polymerase IIstalling promotes nucleosome occlusion and pTEFb recruitment to driveimmortalization by Epstein-Barr virus,” PLoS Pathog 7(10):e1002334(2011); Poreba, E., et al., “Epigenetic mechanisms in virus-inducedtumorigenesis,” Clin Epigenetics 2(2):233-47. 2011. In anotherembodiment, because of their ability to reactivate HIV-1 in models oflatent T cell infection and latent monocyte infection, BET inhibitorscould be used in combination with anti-retroviral therapeutics fortreating HIV. Zhu, J., et al., “Reactivation of Latent HIV-1 byInhibition of BRD4,” Cell Rep (2012); Banerjee, C., et al., “BETbromodomain inhibition as a novel strategy for reactivation of HIV-1,” JLeukoc Biol (2012); Bartholomeeusen, K., et al., “BET bromodomaininhibition activates transcription via a transient release of P-TEFbfrom 7SK snRNP,” J Biol Chem (2012); Li, Z., et al., “The BETbromodomain inhibitor JQ1 activates HIV latency through antagonizingBrd4 inhibition of Tat-transactivation,” Nucleic Acids Res (2012.)

In one embodiment, because of the role of epigenetic processes andbromodomain-containing proteins in neurological disorders, BET inhibitorcompounds of Formula I, Formula Ia, and/or Formula II, stereoisomers,tautomers, pharmaceutically acceptable salts, or hydrates thereof, orcompositions comprising one or more of those compounds may be used totreat diseases including, but not limited to, Alzheimer's disease,Parkinson's disease, Huntington disease, bipolar disorder,schizophrenia, Rubinstein-Taybi syndrome, and epilepsy. Prinjha, R. K.,J. Witherington, and K. Lee, “Place your BETs: the therapeutic potentialof bromodomains,” Trends Pharmacol Sci 33(3):146-53 (2012); Muller, S.,et al., “Bromodomains as therapeutic targets,” Expert Rev Mol Med 13:e29(2011).

In one embodiment, because of the effect of BRDT depletion or inhibitionon spermatid development, BET inhibitor compounds of Formula I, FormulaIa, and/or Formula II, stereoisomers, tautomers, pharmaceuticallyacceptable salts, or hydrates thereof, or compositions comprising one ormore of those compounds may be used as reversible, male contraceptiveagents. Matzuk, M. M., et al., “Small-Molecule Inhibition of BRDT forMale Contraception,” Cell 150(4): p. 673-684 (2012); Berkovits, B. D.,et al., “The testis-specific double bromodomain-containing protein BRDTforms a complex with multiple spliceosome components and is required formRNA splicing and 3′-UTR truncation in round spermatids,” Nucleic AcidsRes 40(15):7162-75 (2012).

Pharmaceutical Compositions

Pharmaceutical compositions of the present disclosure comprise at leastone compound of Formulae I-II, or tautomer, stereoisomer,pharmaceutically acceptable salt or hydrate thereof formulated togetherwith one or more pharmaceutically acceptable carriers. Theseformulations include those suitable for oral, rectal, topical, buccaland parenteral (e.g., subcutaneous, intramuscular, intradermal, orintravenous) administration. The most suitable form of administration inany given case will depend on the degree and severity of the conditionbeing treated and on the nature of the particular compound being used.

Formulations suitable for oral administration may be presented indiscrete units, such as capsules, cachets, lozenges, or tablets, eachcontaining a predetermined amount of a compound of the presentdisclosure as powder or granules; as a solution or a suspension in anaqueous or non-aqueous liquid; or as an oil-in-water or water-in-oilemulsion. As indicated, such formulations may be prepared by anysuitable method of pharmacy which includes the step of bringing intoassociation at least one compound of the present disclosure as theactive compound and a carrier or excipient (which may constitute one ormore accessory ingredients). The carrier must be acceptable in the senseof being compatible with the other ingredients of the formulation andmust not be deleterious to the recipient. The carrier may be a solid ora liquid, or both, and may be formulated with at least one compounddescribed herein as the active compound in a unit-dose formulation, forexample, a tablet, which may contain from about 0.05% to about 95% byweight of the at least one active compound. Other pharmacologicallyactive substances may also be present including other compounds. Theformulations of the present disclosure may be prepared by any of thewell-known techniques of pharmacy consisting essentially of admixing thecomponents.

For solid compositions, conventional nontoxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose,magnesium carbonate, and the like. Liquid pharmacologicallyadministrable compositions can, for example, be prepared by, forexample, dissolving or dispersing, at least one active compound of thepresent disclosure as described herein and optional pharmaceuticaladjuvants in an excipient, such as, for example, water, saline, aqueousdextrose, glycerol, ethanol, and the like, to thereby form a solution orsuspension. In general, suitable formulations may be prepared byuniformly and intimately admixing the at least one active compound ofthe present disclosure with a liquid or finely divided solid carrier, orboth, and then, if necessary, shaping the product. For example, a tabletmay be prepared by compressing or molding a powder or granules of atleast one compound of the present disclosure, which may be optionallycombined with one or more accessory ingredients. Compressed tablets maybe prepared by compressing, in a suitable machine, at least one compoundof the present disclosure in a free-flowing form, such as a powder orgranules, which may be optionally mixed with a binder, lubricant, inertdiluent and/or surface active/dispersing agent(s). Molded tablets may bemade by molding, in a suitable machine, where the powdered form of atleast one compound of the present disclosure is moistened with an inertliquid diluent.

Formulations suitable for buccal (sub-lingual) administration includelozenges comprising at least one compound of the present disclosure in aflavored base, usually sucrose and acacia or tragacanth, and pastillescomprising the at least one compound in an inert base such as gelatinand glycerin or sucrose and acacia.

Formulations of the present disclosure suitable for parenteraladministration comprise sterile aqueous preparations of at least onecompound of Formulae I-II or tautomers, stereoisomers, pharmaceuticallyacceptable salts, and hydrates thereof, which are approximately isotonicwith the blood of the intended recipient. These preparations areadministered intravenously, although administration may also be effectedby means of subcutaneous, intramuscular, or intradermal injection. Suchpreparations may conveniently be prepared by admixing at least onecompound described herein with water and rendering the resultingsolution sterile and isotonic with the blood. Injectable compositionsaccording to the present disclosure may contain from about 0.1 to about5% w/w of the active compound.

Formulations suitable for rectal administration are presented asunit-dose suppositories. These may be prepared by admixing at least onecompound as described herein with one or more conventional solidcarriers, for example, cocoa butter, and then shaping the resultingmixture.

Formulations suitable for topical application to the skin may take theform of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.Carriers and excipients which may be used include Vaseline, lanoline,polyethylene glycols, alcohols, and combinations of two or more thereof.The active compound (i.e., at least one compound of Formulae l-IV ortautomers, stereoisomers, pharmaceutically acceptable salts, andhydrates thereof) is generally present at a concentration of from about0.1% to about 15% w/w of the composition, for example, from about 0.5 toabout 2%.

The amount of active compound administered may be dependent on thesubject being treated, the subject's weight, the manner ofadministration and the judgment of the prescribing physician. Forexample, a dosing schedule may involve the daily or semi-dailyadministration of the encapsulated compound at a perceived dosage ofabout 1 μg to about 1000 mg. In another embodiment, intermittentadministration, such as on a monthly or yearly basis, of a dose of theencapsulated compound may be employed. Encapsulation facilitates accessto the site of action and allows the administration of the activeingredients simultaneously, in theory producing a synergistic effect. Inaccordance with standard dosing regimens, physicians will readilydetermine optimum dosages and will be able to readily modifyadministration to achieve such dosages.

A therapeutically effective amount of a compound or compositiondisclosed herein can be measured by the therapeutic effectiveness of thecompound. The dosages, however, may be varied depending upon therequirements of the patient, the severity of the condition beingtreated, and the compound being used. In one embodiment, thetherapeutically effective amount of a disclosed compound is sufficientto establish a maximal plasma concentration. Preliminary doses as, forexample, determined according to animal tests, and the scaling ofdosages for human administration is performed according to art-acceptedpractices.

Toxicity and therapeutic efficacy can be determined by standardpharmaceutical procedures in cell cultures or experimental animals,e.g., for determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio LD₅₀/ED₅₀.Compositions that exhibit large therapeutic indices are preferable.

Data obtained from the cell culture assays or animal studies can be usedin formulating a range of dosage for use in humans. Therapeuticallyeffective dosages achieved in one animal model may be converted for usein another animal, including humans, using conversion factors known inthe art (see, e.g., Freireich et al., Cancer Chemother. Reports50(4):219-244 (1966) and Table I for Equivalent Surface Area DosageFactors).

TABLE I Equivalent Surface Area Dosage Factors: To: Mouse Rat Monkey DogHuman From: (20 g) (150 g) (3.5 kg) (8 kg) (60 kg) Mouse  1 ½ ¼ ⅙ 1/12Rat  2 1 ½ ¼ 1/7 Monkey  4 2 1 ⅗ ⅓ Dog  6 4 ⅗ 1 ½ Human 12 7 3 2 1

The dosage of such compounds lies preferably within a range ofcirculating concentrations that include the ED₅₀ with little or notoxicity. The dosage may vary within this range depending upon thedosage form employed and the route of administration utilized.Generally, a therapeutically effective amount may vary with thesubject's age, condition, and gender, as well as the severity of themedical condition in the subject. The dosage may be determined by aphysician and adjusted, as necessary, to suit observed effects of thetreatment.

In one embodiment, a compound of Formulae I-II or a tautomer,stereoisomer, pharmaceutically acceptable salt or hydrate thereof, isadministered in combination with another therapeutic agent. The othertherapeutic agent can provide additive or synergistic value relative tothe administration of a compound of the present disclosure alone. Thetherapeutic agent can be, for example, a statin; a PPAR agonist, e.g., athiazolidinedione or fibrate; a niacin, a RVX, FXR or LXR agonist; abile-acid reuptake inhibitor; a cholesterol absorption inhibitor; acholesterol synthesis inhibitor; a cholesteryl ester transfer protein(CETP), an ion-exchange resin; an antioxidant; an inhibitor of AcylCoAcholesterol acyltransferase (ACAT inhibitor); a tyrophostine; asulfonylurea-based drug; a biguanide; an alpha-glucosidase inhibitor; anapolipoprotein E regulator; a HMG-CoA reductase inhibitor, a microsomaltriglyceride transfer protein; an LDL-lowing drug; an HDL-raising drug;an HDL enhancer; a regulator of the apolipoprotein A-IV and/orapolipoprotein genes; or any cardiovascular drug.

In another embodiment, a compound of Formulae I and/or Formula II or atautomer, stereoisomer, pharmaceutically acceptable salt or hydratethereof, is administered in combination with one or moreanti-inflammatory agents. Anti-inflammatory agents can includeimmunosuppressants, TNF inhibitors, corticosteroids, non-steroidalanti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs(DMARDS), and the like. Exemplary anti-inflammatory agents include, forexample, prednisone; methylprenisolone (Medrol®), triamcinolone,methotrexate (Rheumatrex®, Trexall®), hydroxychloroquine (Plaquenil®),sulfasalzine (Azulfidine®), leflunomide (Arava®), etanercept (Enbrel®),infliximab (Remicade®), adalimumab (Flumira®), rituximab (Rituxan®),abatacept (Orencia®), interleukin-1, anakinra (Kineret™), ibuprofen,ketoprofen, fenoprofen, naproxen, aspirin, acetominophen, indomethacin,sulindac, meloxicam, piroxicam, tenoxicam, lornoxicam, ketorolac,etodolac, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamicacid, diclofenac, oxaprozin, apazone, nimesulide, nabumetone, tenidap,etanercept, tolmetin, phenylbutazone, oxyphenbutazone, diflunisal,salsalate, olsalazine, or sulfasalazine.

EXAMPLES

General Methods. Unless otherwise noted, reagents and solvents were usedas received from commercial suppliers. Proton nuclear magnetic resonancespectra were obtained on a Bruker AVANCE 300 spectrometer at 300 MHz orBruker AVANCE 500 spectrometer at 500 MHz or a Bruker AVANCE 300spectrometer at 300 MHz. Spectra are given in ppm (δ) and couplingconstants, J values, are reported in hertz (Hz). Tetramethylsilane wasused as an internal standard for ¹H nuclear magnetic resonance. Massspectra analyses were performed on Waters Aquity UPLC Mass Spectrometerin ESI or APCI mode when appropriate, Agilent 6130A Mass Spectrometer inESI, APCI, or MultiMode mode when appropriate or Applied BiosystemsAPI-150EX Spectrometer in ESI or APCI mode when appropriate. Silica gelchromatographys were in general performed on a Teledyne Isco CombiFlash®Rf 200 system or a Teledyne Isco CombiFlash® Companion system.

Abbreviations: CDI: 1,1′-carbonyldiimidazole; DMAP:N,N-dimethylaminopropylamine; EDC:1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; m-CPBA:3-chloroperoxybenzoic acid; NBS: N-bromosuccinimide.

General Procedure A Preparation of9-Benzyl-2-(3,5-dimethylisoxazol-4-yl)-9H-purin-6-amine (ExampleCompound 1)

Step 1: To a slurry of 1 (1.50 g, 8.84 mmol) in DMF (50 mL) was addedpotassium carbonate (3.64 g, 26.4 mmol) and benzyl chloride (1.01 mL,8.84 mmol). The reaction was stirred at rt for 16 h. The reactionmixture was filtered, the filtrate was poured into water (100 mL) andstirred for 5 minutes. The solid was collected and dried to give 2 (1.60g, 70%) as a yellow solid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.26 (s, 1H),7.80 (br s, 2H), 7.38-7.26 (m, 5H), 5.34 (s, 2H); ESI m/z 260 [M+H]⁺.

Step 2: To a solution of 2 (260 mg, 1.0 mmol) in 1,4-dioxane (10 mL) andDMF (4 mL) was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(335 mg, 1.5 mmol), sodium carbonate (2.0 M in H₂O, 1.0 mL, 2.0 mmol)and tetrakis(triphenylphosphine) palladium(0) (116 mg, 0.1 mmol). Thereaction mixture was purged with nitrogen and heated at 80° C. for 16 h.The mixture was diluted with methylene chloride (20 mL) and filtered.The filtrate was concentrated and purified by chromatography (silicagel, 0-5% methylene chloride/methanol) followed by trituration withEtOAc/hexanes to afford9-benzyl-2-(3,5-dimethylisoxazol-4-yl)-9H-purin-6-amine (ExampleCompound 1) (110 mg, 34%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ8.29 (s, 1H), 7.36-7.28 (m, 7H), 5.38 (s, 2H), 2.73 (s, 3H), 2.51 (s,3H); ESI m/z 321 [M+H]⁺.

Preparation of3-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one(Example Compound 2)

Step 1: To a solution of 4 (500 mg, 2.66 mmol) in 1,4-dioxane (15 mL)was added CDI (517 mg, 3.19 mmol). The reaction was heated at 60° C. for16 h. The solid was collected and dried to give 5 (340 mg, 60%) as alight purple solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.58 (br s, 1H), 11.02(br s, 1H), 7.19 (d, J=8.1 Hz, 1H), 7.13 (d, J=8.1 Hz, 1H).

Step 2: To a solution of 5 (170 mg, 0.79 mmol) in 1,4-dioxane (12 mL)and DMF (6 mL) was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(352 mg, 1.58 mmol), sodium carbonate (2.0 M in H₂O, 1.19 mL, 2.37 mmol)and tetrakis(triphenylphosphine) palladium(O) (92 mg, 0.08 mmol). Thereaction mixture was purged with nitrogen and heated at 80° C. for 16 h.The mixture was diluted with methylene chloride (20 mL) and filtered.The filtrate was concentrated and purified by chromatography (silicagel, 0-5% methylene chloride/methanol) to afford 6 (130 mg, 71%) as awhite solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.38 (br s, 1H), 10.90 (br s,1H), 7.30 (d, J=7.8 Hz, 1H), 7.07 (d, J=8.1 Hz, 1H), 2.49 (s, 3H), 2.33(s, 3H).

Step 3: To a solution of 6 (100 mg, 0.43 mmol) in DMF (10 mL) was addedpotassium carbonate (72 mg, 0.52 mmol) and di-tert-butyl dicarbonate(104 mg, 0.48 mmol). The reaction was stirred at rt for 16 h. To thereaction mixture was added potassium carbonate (72 mg, 0.52 mmol) andbenzyl chloride (0.14 mL, 0.48 mmol). The reaction was stirred at rt for16 h. The mixture was diluted with EtOAc (100 mL) and washed with brine(50 mL). The organic layer was dried over sodium sulfate, filtered andconcentrated. Purification by chromatography (silica gel, 0-30% ethylacetate/hexanes) afforded 6 (130 mg, 71%) as a colorless gum: ¹H NMR(300 MHz, DMSO-d₆) δ 7.97 (d, J=8.1 Hz, 1H), 7.38-7.27 (m, 6H), 5.05 (s,2H), 2.49 (s, 3H), 2.29 (s, 3H), 1.61 (s, 9H).

Step 4: A solution of 7 (130 mg, 0.31 mmol) in methylene chloride (4 mL)and TFA (2 mL) was stirred at rt for 2 h. The mixture was concentrated,the residue was dissolved in methylene chloride (100 mL), washed withsaturated NaHCO₃ (50 mL×2) and brine (50 mL). The organic layer wasdried over sodium sulfate, filtered and concentrated to afford3-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one(Example Compound 2) (81 mg, 81%) as an off-white solid: ¹H NMR (300MHz, DMSO-d₆) δ 11.31 (s, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.34-7.25 (m,5H), 7.15 (d, J=7.8 Hz, 1H), 5.03 (s, 2H), 2.47 (s, 3H), 2.28 (s, 3H);ESI m/z 321 [M+H]⁺.

Preparation of1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one(Example Compound 3)

Step 1: To a solution of 4 (500 mg, 2.66 mmol) and benzaldehyde (282 mg,2.66 mmol) in methylene chloride (15 mL) was added acetic acid (319 mg,5.32 mmol). The reaction was stirred at rt for 30 minutes, thenNaBH(OAc)₃ (1.69 g, 7.98 mmol) was added. The reaction mixture wasstirred at rt for 16 h. The mixture was diluted with methylene chloride(100 mL) and saturated aq. NaHCO₃ (50 mL) was added slowly. The organiclayer was separated, dried over sodium sulfate, filtered andconcentrated. The residue was triturated with methylene chloride/EtOActo give 8 (401 mg, 54%) as a light brown solid: ¹H NMR (300 MHz,DMSO-d₆) δ 7.34-7.22 (m, 5H), 6.48 (d, J=7.8 Hz, 1H), 6.40 (d, J=7.8 Hz,1H), 6.02 (br s, 2H), 5.54 (t, J=5.7 Hz, 1H), 4.27 (d, J=5.4 Hz, 2H).

Step 2: To a solution of 8 (400 mg, 1.44 mmol) in 1,4-dioxane (10 mL)was added CDI (514 mg, 3.17 mmol). The reaction was heated at 110° C.for 16 h. The reaction mixture was concentrated. Purification bychromatography (silica gel, 0-40% ethyl acetate/hexanes) afforded 9 (310mg, 71%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.96 (s, 1H),7.35-7.27 (m, 6H), 7.19 (d, J=7.8 Hz, 1H), 5.02 (s, 2H).

Step 3: To a solution of 9 (310 mg, 1.02 mmol) in 1,4-dioxane (10 mL)was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(341 mg, 1.53 mmol), sodium carbonate (2.0 M in H₂O, 1.02 mL, 2.04 mmol)and tetrakis(triphenylphosphine)palladium(0) (59 mg, 0.05 mmol). Thereaction mixture was purged with nitrogen and heated at 80° C. for 16 h.The mixture was diluted with methylene chloride (20 mL) and filtered.The filtrate was concentrated and the residue was purified bychromatography (silica gel, 0-80% EtOAc/hexanes) and trituration withEtOAc to afford1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one(Example Compound 3) (202 mg, 62%) as a white solid: ¹H NMR (300 MHz,DMSO-d₆) δ 11.76 (s, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.36-7.28 (m, 5H),7.11 (d, J=7.8 Hz, 1H), 5.05 (s, 2H), 2.49 (s, 3H), 2.32 (s, 3H); ESIm/z 321 [M+H]⁺.

General Procedure B Preparation of4-(3-Benzyl-3H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole(Example Compound 4) and4-(1-Benzyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole(Example Compound 5)

Step 1: To a solution of 10 (400 mg, 2.0 mmol) in 1,4-dioxane (10 mL)was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(669 mg, 1.5 mmol), sodium carbonate (2.0 M in H₂O, 2.0 mL, 4.0 mmol)and tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.1 mmol). Thereaction mixture was purged with nitrogen and heated at 80° C. for 16 h.The mixture was concentrated and purified by chromatography (silica gel,0-8% methylene chloride/methanol) followed by trituration withEtOAc/hexanes to afford 11 (228 mg, 53%) as a light yellow solid: ESIm/z 215 [M+H]⁺.

Step 2: To a solution of 11 (220 mg, 1.03 mmol) in CH₃CN (10 mL) wasadded potassium carbonate (426 mg, 3.09 mmol) and benzyl chloride (0.12mL, 1.03 mmol). The reaction was stirred at rt for 16 h. The mixture wasconcentrated and purified by chromatography (silica gel, 0-10%methanol/methylene chloride) to afford4-(3-benzyl-3H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole(Example Compound 4) (34 mg, 11%) as an off-white solid: ¹H NMR (300MHz, CDCl₃) δ 8.34 (d, J=1.8 Hz, 1H), 8.14 (s, 1H), 7.99 (d, J=1.8 Hz,1H), 7.40-7.31 (m, 5H), 5.52 (s, 2H), 2.44 (s, 3H), 2.30 (s, 3H); ESIm/z 305 [M+H]⁺;4-(1-benzyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole(Example Compound 5) (39 mg, 12%) as an off-white solid: ¹H NMR (300MHz, CDCl₃) δ 8.46 (d, J=1.8 Hz, 1H), 8.29 (s, 1H), 7.40-7.37 (m, 3H),7.34 (d, J=2.1 Hz, 1H), 7.24-7.21 (m, 2H), 5.41 (s, 2H), 2.33 (s, 3H),2.16 (s, 3H); ESI m/z 305 [M+H]⁺.

Preparation of3-Benzyl-5-(3,5-dimethylisoxazol-4-yl)benzo[d]oxazol-2(3H)-one (ExampleCompound 6)

Step 1: To a solution of 13 (5.00 g, 22.9 mmol) in acetic acid (50 mL),ethanol (100 mL), and water (5 mL) was added iron powder (6.42 g, 115mmol). The reaction was heated at 80° C. for 2 h under nitrogen. Thereaction mixture was cooled to room temperature, concentrated andpurified by chromatography (silica gel, 0-100% hexanes/ethyl acetate) togive 14 (3.27 g, 76%) as a brown solid: ¹H NMR (300 MHz, CDCl₃) δ 6.88(d, J=2.2 Hz, 1H), 6.77 (dd, J=8.3, 2.3 Hz, 1H), 6.60 (d, J=8.3 Hz, 1H),6.00-5.20 (br s, 3H).

Step 2: To a solution of 14 (1.50 g, 7.98 mmol) in 1,4-dioxane (100 mL)was added 1,1′-carbonyldiimidazole (1.55 g, 9.58 mmol). The reaction washeated at 80° C. for 17 h under nitrogen. The mixture was cooled to roomtemperature and 2N aq. HCl (40 mL) was added. The solution was dilutedwith ethyl acetate (200 mL) and washed with brine (2×50 mL). The organiclayer was dried over sodium sulfate, filtered and concentrated.Purification by chromatography (silica gel, 0-50% ethyl acetate/hexanes)afforded 15 (1.08 g, 63%) as an orange solid: ¹H NMR (500 MHz, DMSO-d₆)δ 11.81 (s, 1H), 7.27-7.25 (m, 3H).

Step 3: To a solution of 15 (150 mg, 0.701 mmol) in acetonitrile (10 mL)was added benzyl bromide (180 mg, 1.05 mmol) and potassium carbonate(193 mg, 1.40 mmol). The reaction was heated at 80° C. for 3 h. Thereaction mixture was cooled to room temperature, concentrated andpurified by chromatography (silica gel, 0-50% ethyl acetate/hexanes) toafford 16 (195 mg, 92%) as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ7.41-7.30 (m, 5H), 7.22 (dd, J=8.5, 1.7 Hz, 1H), 7.08 (d, J=8.5 Hz, 1H),6.97 (d, J=1.6 Hz, 1H), 4.97 (s, 2H).

Step 4: To a solution of 16 (195 mg, 0.641 mmol) in 1,4-dioxane (10 mL)was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(172 mg, 0.769 mmol), potassium carbonate (177 mg, 1.28 mmol), andtetrakis(triphenylphosphine)palladium(0) (37 mg, 0.032 mmol). Thereaction mixture was purged with nitrogen and heated at 100° C. for 4 h.The reaction mixture was cooled to room temperature, concentrated andpurified by chromatography (silica gel, 0-30% ethyl acetate/hexanes). Itwas further purified by reverse phase HPLC on Polaris column elutingwith 10-90% CH₃CN in H₂O to give3-benzyl-5-(3,5-dimethylisoxazol-4-yl)benzo[d]oxazol-2(3H)-one (ExampleCompound 6) (115 mg, 56%) as an off-white solid: ¹H NMR (500 MHz,DMSO-d₆) δ 7.47-7.42 (m, 3H), 7.40-7.34 (m, 2H), 7.34-7.28 (m, 1H), 7.23(d, J=1.6 Hz, 1H), 7.12 (dd, J=8.2 Hz, 7.7 Hz, 1H), 5.07 (s, 2H), 2.33(s, 3H), 2.15 (s, 3H); ESI m/z 321 [M+H]⁺.

General Procedure C Preparation of1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine(Example Compound 7),1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-7-amine(Example Compound 8) andN,1-Dibenzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine(Example Compound 9)

To a solution of6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine 17 (290 mg,1.27 mmol) in CH₃CN (15 mL) was added potassium carbonate (350 mg, 2.54mmol) and benzyl chloride (200 mg, 1.59 mmol). The reaction mixture wasstirred at 60° C. for 16 h. The mixture was diluted with methylenechloride (20 mL) and filtered through a layer of Celite. The filtratewas concentrated and purified by chromatography (silica gel, 0-10%CH₃OH/CH₂Cl₂) to afford1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine(Example Compound 7) (109 mg, 27%) as an off-white solid: ¹H NMR (300MHz, CDCl₃) δ 7.95 (s, 1H), 7.37-7.34 (m, 3H), 7.23-7.20 (m, 2H), 6.46(d, J=1.2 Hz, 1H), 6.40 (d, J=1.2 Hz, 1H), 5.34 (s, 2H), 2.31 (s, 3H),2.16 (s, 3H); ESI MS m/z 319 [M+H]⁺;1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-7-amine(Example Compound 8) (19 mg, 4.7%) as an off-white solid: ¹H NMR (300MHz, CDCl₃) δ 8.15 (s, 1H), 7.43-7.40 (m, 3H), 7.23 (d, J=1.2 Hz, 1H),7.20-7.17 (m, 2H), 6.39 (d, J=1.2 Hz, 1H), 5.69 (s, 2H), 2.40 (s, 3H),2.27 (s, 3H); ESI MS m/z 319 [M+H]⁺;N,1-dibenzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine(Example Compound 9) (40 mg, 8%) as an off-white solid: ¹H NMR (300 MHz,DMSO-d₆) δ 8.27 (s, 1H), 7.40-7.18 (m, 10H), 6.62 (d, J=1.2 Hz, 1H),6.57 (t, J=6.0 Hz, 1H), 5.97 (d, J=1.2 Hz, 1H), 5.41 (s, 2H), 4.48 (d,J=6.0 Hz, 2H), 2.12 (s, 3H), 1.94 (s, 3H); ESI MS m/z 409 [M+H]⁺.

Preparation of1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one(Example Compound 10)

1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one(Example Compound 10) was prepared by following the method for thepreparation of Example 3 affording the product (158 mg, 47%) as a whitesolid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.81 (s, 1H), 7.90 (d, J=2.1 Hz,1H), 7.44-7.25 (m, 6H), 5.05 (s, 2H), 2.34 (s, 3H), 2.16 (s, 3H); MM m/z321 [M+H]⁺.

Preparation of1-Benzyl-7-(3,5-dimethylisoxazol-4-yl)quinoxalin-2(1H)-one (ExampleCompound 11)

Step 1: A solution of 18 (500 mg, 2.3 mmol), benzylamine (1.2 g, 11.4mmmol) and pyridine (5.0 mL) was stirred at room temperature for 18hours. The solvent was removed in vacuo and the product was purified bychromatography (silica gel, 0-10% ethyl acetate/hexanes) to provide 19(630 mg, 91%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 8.38 (s, 1H),8.05 (d, J=9.1 Hz, 1H), 7.40-7.32 (m, 5H), 7.01 (d, J=1.9 Hz, 1H), 6.79(dd, J=9.1, 1.9 Hz, 1H), 4.51 (d, J=5.5 Hz, 2H).

Step 2: A mixture of 19 (100 mg, 0.33 mmol), iron powder (127 mg, 2.28mmol), ammonium chloride (27 mg, 0.5 mmol), water (0.5 mL) and ethanol(3 mL) was heated at reflux for 0.5 hour. The reaction mixture wascooled and filtered. The solvent was removed to provide 20 (90 mg, 100%)as an off-white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.40-7.29 (m, 5H),6.81-6.77 (m, 2H), 6.61-6.58 (m, 1H), 4.27 (s, 2H), 3.41 (s, 1H); ESIm/z 212, [M+H]⁺.

Step 3: To a mixture of 20 (100 mg, 0.36 mmol), triethylamine (48 mg,0.47 mmol), CH₂Cl₂ (0.5 mL) and THF (1.0 mL) was added a solution ofethyl bromoacetate (78 mg, 0.47 mmol) in THF (1.0 mL) at roomtemperature. The reaction mixture was stirred for 18 hours and thenheated to 75° C. for 1 hour. The reaction mixture was concentrated andthe product purified by chromatography (silica gel, 0-30% ethylacetate/hexanes) to provide 21 (44 mg, 39%) as a tan solid: ¹H NMR (500MHz, CDCl₃) δ 7.38-7.29 (m, 4H), 7.24-7.22 (m, 2H), 6.98-6.93 (m, 2H),6.55 (d, J=8.3 Hz, 1H), 5.13 (s, 2H), 4.05 (s, 2H); ESI m/z 318 [M+H]⁺.

Step 4: A mixture of 21 (44 mg, 0.14 mmol), 3 (47 mg, 0.21 mmol), K₂CO₃(39 mg, 0.28 mmol), tetrakis(triphenylphosphine)palladium(0) (8 mg, 0.01mmol), 1,4-dioxane (3 mL) and water (0.5 mL) was heated at 90° C. for 16hours. The reaction mixture was concentrated onto silica gel and theproduct purified by chromatography (silica gel, 0-50% ethylacetate/hexanes) to provide1-benzyl-7-(3,5-dimethylisoxazol-4-yl)quinoxalin-2(1H)-one (ExampleCompound 11) (16 mg, 34%) as an off-white solid: ¹H NMR (300 MHz, CDCl₃)δ 8.43 (s, 1H), 7.94 (d, J=8.2 Hz, 1H), 7.35-7.32 (m, 2H), 7.29-7.27 (m,1H), 7.21-7.18 (m, 3H), 7.04 (s, 1H), 5.51 (s, 1H), 2.16 (s, 3H), 2.02(s, 3H); ESI m/z 332 [M+H]⁺.

Preparation of1-Benzyl-7-(3,5-dimethylisoxazol-4-yl)-3,4-dihydroquinazolin-2(1H)-one(Example Compound 12)

Step 1: To a solution of 22 (1.19 g, 5.53 mmol) and benzaldehyde (594mg, 5.60 mmol) in CH₂Cl₂ (50 mL) and CH₃CN (50 mL) was added acetic acid(0.2 mL). The mixture was stirred at rt for 1 h. NaBH(OAc)₃ (3.52 g,16.59 mmol) was added. The mixture was stirred at rt for 8 h. Thereaction was quenched with saturated aq. NaHCO₃ (50 mL) andconcentrated, the residue was suspended in EtOAc (300 mL), washed withbrine (100 mL). The organic layer was separated, dried over sodiumsulfate, filtered and concentrated. The residue was purified bychromatography (silica gel, 0-50% EtOAc/heptane) to afford 23 (201 mg,12%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.75 (d, J=5.7Hz, 1H), 7.93 (br.s, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.38-7.31 (m, 6H),6.76 (d, J=1.8 Hz, 1H), 6.69 (dd, J=8.4, 1.8 Hz, 1H), 4.39 (d, J=6.0 Hz,2H).

Step 2: To a solution of 23 (518 mg, 1.70 mmol) in THF (20 mL) was addedBH₃.THF (1.0 M in THF, 8.50 mL, 8.50 mmol). The mixture was heated toreflux for 16 h. MeOH (40 mL) was added slowly followed by 2 N HCl (40mL). The mixture was heated to reflux for 3 h. NH₄OH (60 mL) was added,the mixture was extracted with EtOAc (200 mL×3). The organic layer wasseparated, dried over sodium sulfate, filtered and concentrated. Theresidue was purified by chromatography (silica gel, 0-10% MeOH/methylenechloride) to afford 24 (372 mg, 75%) as an colorless gum: ¹H NMR (300MHz, DMSO-d₆) δ 7.32-7.21 (m, 5H), 6.98 (d, J=7.8 Hz, 1H), 6.87 (t,J=6.0 Hz, 1H), 6.65 (dd, J=8.1, 2.1 Hz, 1H), 6.53 (d, J=2.1 Hz, 1H),4.33 (d, J=5.7 Hz, 2H), 3.71 (s, 2H), 1.92 (br.s, 2H).

Step 3: Using the procedure used for Example Compound 3 step 2 startingwith compound 24 (362 mg, 1.24 mmol) afforded 25 (325 mg, 85%) as ayellow solid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.33-7.31 (m, 3H), 7.25-7.23(m, 3H), 7.09 (d, J=1.8 Hz, 2H), 6.86 (s, 1H), 5.05 (s, 2H), 4.35 (d,J=1.5 Hz, 2H).

Step 4: Using the procedure used for Example Compound 3 step 3 startingwith compound 25 (317 mg, 1.00 mmol) afforded Example Compound 12 (199mg, 60%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 7.34-7.21 (m,7H), 6.90 (dd, J=7.5, 1.0 Hz, 1H), 6.58 (d, J=1.0 Hz, 1H), 5.09 (s, 2H),4.43 (s, 2H), 2.06 (s, 3H), 1.89 (s, 3H); MM m/z 334 [M+H]⁺.

General Procedure D Preparation of4-(1-benzyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazol(Example Compound 13)

Step 1: To a mixture of 26 (1.00 g, 5.32 mmol) and 3 (1.78 g, 7.98 mmol)in 1,4-dioxane (35 mL) and water (7.5 mL) was added potassium carbonate(1.47 g, 10.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (307mg, 0.27 mmol). The reaction was stirred and heated at 90° C. for 16 h.The reaction mixture was diluted with methanol (20 mL) and silica gel(15 g) was added. The slurry was concentrated to dryness and theresulting powder was loaded onto silica gel and eluted with 0-90% ethylacetate in hexanes. The clean product was concentrated to give 27 (939mg, 70%) as a yellow-green solid: ¹H NMR (500 MHz, CDCl₃) δ 7.45 (t,J=2.0 Hz, 1H), 6.78 (t, J=2.0 Hz, 1H), 2.37 (s, 3H), 2.22 (s, 3H).

Step 2: To a solution of 27 (300 mg, 1.47 mmol) in 1,2-dichloroethane(15 mL) was added benzaldehyde (156 mg, 1.47 mmol) and glacial aceticacid (200 μL) at room temperature. After stirring for 17 h, CH₂Cl₂ (20mL) then saturated aq. NaHCO₃ (20 mL, slowly) was added. The organiclayer was separated and dried over Na₂SO₄. The suspension was filteredand concentrated. The material was purified by chromatography (silicagel, 0-60% ethyl acetate in hexanes) to afford a yellow solid which wasdissolved in methanol (10 mL), sodium borohydride (52 mg, 1.35 mmol) wasadded at room temperature. After stirring for 1 h, additional sodiumborohydride (156 mg, 3.40 mmol) was added and the reaction stirred 1 h.A 2N aq. HCl solution was added to the mixture until pH 4 (2 mL) then asaturated NaHCO₃ solution was added to basify to pH 8 (2 mL). Water wasadded (10 mL) and the solution was extracted with ethyl acetate (3×100mL). The ethyl acetate extracts were combined, dried over Na₂SO₄,filtered and concentrated to afford 28 (401 mg, 93%) as a white solid:¹H NMR (500 MHz, CDCl₃) δ 7.48 (s, 1H), 7.37-7.26 (m, 5H), 6.58 (s, 1H),4.38 (s, 2H), 4.33 (br s, 2H), 3.77 (br s, 1H), 2.24 (s, 3H), 2.08 (s,3H).

Step 3: To 28 (350 mg, 1.19 mmol) was added triethylorthoacetate (3.0mL, 16.4 mmol) and sulfamic acid (1 mg). The mixture was heated to 100°C. for 1 h. The mixture was diluted with methanol (20 mL) and adsorbedonto silica gel (10 g). The material was purified by chromatography(silica gel, 0-60% ethyl acetate in hexanes then 0-5% methanol inCH₂Cl₂) to afford4-(1-benzyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole(Example Compound 13, 169 mg, 45%) as a white solid: ¹H NMR (500 MHz,CD₃OD) δ 8.32 (d, J=1.0 Hz, 1H), 7.78 (d, J=1.0 Hz, 1H), 7.36-7.29 (m,3H), 7.20-7.17 (m, 2H), 5.56 (s, 2H), 2.69 (s, 3H), 2.36 (s, 3H), 2.18(s, 3H); ESI m/z 319 [M+H]⁺.

General Procedure E Preparation of1-(4-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one(Example Compound 91) and4-Amino-1-(4-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one(Example Compound 90)

Step 1: To a solution of 29 (1.00 g, 4.61 mmol) in 1,4-dioxane (40 mL)and water (4 mL) was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(1.23 g, 5.53 mmol), potassium carbonate (1.27 g, 9.22 mmol), andtetrakis(triphenylphosphine)palladium(0) (266 mg, 0.231 mmol). Thereaction mixture was purged with nitrogen and heated at 90° C.overnight. The reaction mixture was cooled to room temperature,concentrated and purified by chromatography (silica gel, 0-30% ethylacetate/hexanes) to give a yellow solid which was dissolved in aceticacid (15 mL), N-bromosuccinimide (753 mg, 4.23 mmol) was added at 0° C.The reaction was warmed to room temperature and stirred overnight. Themixture was concentrated in vacuo. The residue was suspended in hotMeOH, cooled to room temperature and basified with 10% aq. NaHCO₃. Themixture was diluted with water and filtered. The filter cake was washedwith water and dried in vacuo to afford 30 (1.10 g, 87%) as a yellowsolid: ¹H NMR (500 MHz, CDCl₃) δ 8.04 (d, J=2.1 Hz, 1H), 7.61 (d, J=2.1Hz, 1H), 6.69 (bs, 2H), 2.40 (s, 3H), 2.26 (s, 3H); ESI m/z 312 [M+H]⁺.

Step 2: To a solution of 30 (500 mg, 1.60 mmol) in toluene (50 mL) undernitrogen atmosphere was added 4-chlorobenzylamine (1.36 g, 9.62 mmol),cesium carbonate (1.04 g, 3.02 mmol),2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (114 mg,0.240 mmol), and tris(dibenzylideneacetone)dipalladium(0) (146 mg, 0.160mmol). The reaction mixture was heated at 90° C. overnight, cooled toroom temperature, and purified by chromatography (silica gel, 0-50%ethyl acetate in hexanes) to afford 31 (290 mg, 49%) as a red solid: ESIm/z 373 [M+H]⁺.

Step 3: To a mixture of 31 (290 mg, 0.779 mmol) in 1,4-dioxane (10 mL)was added 1,1′-carbonyldiimidazole (630 mg, 3.89 mmol) and DMAP (acrystal). The reaction was heated in a sealed tube at 130° C. for 4days. The mixture was concentrated and purified by chromatography(silica gel, 0-100% ethyl acetate in hexanes) to give Example Compound91 (144 mg, 46%) as an orange solid: ¹H NMR (500 MHz, CD₃OD) δ 7.80 (d,J=1.4 Hz, 1H), 7.40-7.35 (m, 4H), 7.24 (d, J=1.4 Hz, 1H), 5.15 (s, 2H),2.32 (s, 3H), 2.15 (s, 3H); ESI m/z 399 [M+H]⁺.

Step 4: To a solution of Example Compound 91 (70 mg, 0.18 mmol) intetrahydrofuran (10 mL) was added sodium dithionite (183 mg, 1.05 mmol)in water (10 mL). The reaction mixture was stirred at room temperatureovernight and concentrated under vacuum. To the residue was added 2N HCland heated to reflux, cooled to room temperature, and concentrated invacuum. The residue was dissolved in MeOH and basified by cone. NH₄OH,concentrated, and purified by chromatography (silica gel, 0-100%hexanes/ethyl acetate). It was further purified by reverse phase HPLC ona Polaris Cig column eluting with 10-90% CH₃CN in H₂O to give ExampleCompound 90 (34 mg, 51%) as an off-white solid: ¹H NMR (500 MHz, CD₃OD)δ 7.36-7.28 (m, 4H), 6.40 (d, J=1.4 Hz, 1H), 6.25 (d, J=1.4 Hz, 1H),5.03 (s, 2H), 2.28 (s, 3H), 2.12 (s, 3H); ESI m/z 369 [M+H]⁺.

General Procedure F Preparation of4-(1-(cyclopropylmethyl)-2-methyl-4-nitro-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole(Example Compound 14) and1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-amine(Example Compound 75)

Step 1: A solution of 32 (488 mg, 2.10 mmol) and 2,4-pentanedione (421mg, 4.21 mmol) in absolute ethanol (28 mL) and 5 N aq. HCl (7.8 mL) washeated to reflux for 3 h. The mixture was concentrated to dryness andethyl acetate was added (200 mL). The solution was washed with saturatedaq. NaHCO₃ (250 mL) and saturated aq. NaCl solution (250 mL), dried overNa₂SO₄, filtered and concentrated. The residue was purified bychromatography (silica gel, 0-40% hexanes/ethyl acetate) to afford 33(495 mg, 92%) as a orange solid: ¹H NMR (500 MHz, CDCl₃) δ 10.38 (br s,1H), 8.24 (d, J=2.0 Hz, 1H), 8.12 (d, J=1.0 Hz, 1H), 2.73 (s, 3H).

Step 2: To a mixture of 33 (200 mg, 0.78 mmol) and 3 (262 mg, 1.17 mmol)in 1,4-dioxane (6 mL) and water (1.5 mL) was added potassium carbonate(216 mg, 1.56 mmol) and tetrakis(triphenylphosphine)palladium(0) (45 mg,0.04 mmol). The reaction was stirred and heated at 90° C. for 17 h. Thereaction mixture was diluted with methanol (20 mL) and silica gel (15 g)was added. The suspension was concentrated to dryness and the resultingpowder was purified by chromatography (silica gel, 0-90% hexanes/ethylacetate) to give 34 (187 mg, 88%) as a yellow solid: ¹H NMR (500 MHz,CDCl₃) δ 8.00 (d, J=1.5 Hz, 1H), 7.89 (s, 1H), 2.76 (s, 3H), 2.45 (s,3H), 2.30 (s, 3H).

Step 3: To a solution of 34 (217 mg, 0.797 mmol), potassium carbonate(220 mg, 1.59 mmol), acetonitrile (5 mL) and DMF (1 mL) was addedbromomethylcyclopropane (129 mg, 0.956 mmol) and the reaction was heatedat 60° C. for 17 h. The material was cooled to room temperature andpoured into a saturated aq. NaCl solution (30 mL). Ethyl acetate (100mL) was added and the layers were separated. The ethyl acetate layer waswashed with saturated aq. NaCl solution (2×20 mL), dried over Na₂SO₄,filtered and concentrated. The residue was purified by chromatography(silica gel, 0-90% hexanes/ethyl acetate) to give Example 14 (178 mg,68%) as an yellow solid: ¹H NMR (500 MHz, CD₃OD) δ 8.03 (d, J=1.5 Hz,1H), 7.93 (d, J=1.5 Hz, 1H), 4.27 (d, J=7.0 Hz, 2H), 2.75 (s, 3H), 2.46(s, 3H), 2.30 (s, 3H), 1.38-1.28 (m, 1H), 0.65-0.60 (m, 2H), 0.51-0.46(m, 2H). ESI m/z 327 [M+H]⁺

Step 4: To a solution of Example Compound 14 (160 mg, 0.51 mmol) in THF(10 mL) was added a solution of sodium dithionite (446 mg, 2.56 mmol) inwater (10 mL) dropwise over 5 min. The solution was stirred at roomtemperature for 16 h and the solvents were removed in vacuo. Methanol(20 mL) was added and the suspension stirred at room temperature for 3h. The mixture was filtered and the filtrate was concentrated todryness. A solution of 2N aq. HCl (10 mL) was added to the residue andwas heated to reflux for 5 min. After concentration to dryness, methanol(20 mL) was added and the solution was adjusted to pH 8 using saturatedaq. NaHCO₃ solution (10 mL). Silica gel was added (10 g) and thesuspension was concentrated to dryness. The resulting powder waspurified by chromatography (silica gel, 0-5% methanol/methylenechloride), the product was then purified by reverse phase HPLC on aPolaris Cig column eluting with 10-90% CH₃CN in H₂O to give ExampleCompound 75 (131 mg, 99%) as a white solid: ¹H NMR (500 MHz, CD₃OD) δ6.70 (s, 1H), 6.44 (d, J=1.0 Hz, 1H), 4.08 (d, J=6.5 Hz, 2H), 2.61 (s,3H), 2.40 (s, 3H), 2.25 (s, 3H), 1.30-1.19 (m, 1H), 0.62-0.53 (m, 2H),0.45-0.40 (m, 2H). ESI m/z 297 [M+H]⁺.

General Procedure G Preparation of1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one(Example Compound 15) and4-amino-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one(Example Compound 16)

Step 1: To a solution of 32 (232 mg, 1.0 mmol) in 1,4-dioxane (5 mL) wasadded CDI (194 mg, 1.2 mmol). The reaction was heated at 60° C. for 16h. The solid was collected and dried to give 35 (202 mg, 78%) as a brownyellow solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.83 (br s, 1H), 11.53 (br s,1H), 7.86 (d, J=1.8 Hz, 1H), 7.43 (d, J=1.8 Hz, 1H).

Step 2: To a solution of 35 (200 mg, 0.78 mmol) in DMF (7 mL) was addedpotassium carbonate (118 mg, 0.85 mmol) and benzyl chloride (98 mg, 0.78mmol). The reaction was stirred at rt for 16 h. The mixture was dilutedwith EtOAc (100 mL) and washed with brine (50 mL). The organic layer wasdried over sodium sulfate, filtered and concentrated. Purification bychromatography (silica gel, 0-100% ethyl acetate/hexanes) afforded 36(101 mg, 37%) as a yellow solid: ¹H NMR (300 MHz, DMSO-d₆) δ 12.15 (s,1H), 7.90 (d, J=0.9 Hz, 1H), 7.75 (d, J=1.2 Hz, 1H), 7.36-7.28 (m, 5H),5.10 (s, 2H).

Step 3: To a solution of 36 (100 mg, 0.29 mmol) in 1,4-dioxane (7 mL)was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(128 mg, 0.57 mmol), sodium carbonate (2.0 M in H₂O, 0.43 mL, 0.86 mmol)and tetrakis(triphenylphosphine)palladium(0) (34 mg, 0.03 mmol). Thereaction mixture was purged with nitrogen and heated at 80° C. for 16 h.The mixture was diluted with methylene chloride (20 mL) and filtered.The filtrate was concentrated and purified by chromatography (silicagel, 10-50% ethyl acetate/hexanes) followed by trituration with ethylacetate to afford Example Compound 15 (70 mg, 66%) as a yellow solid: ¹HNMR (300 MHz, DMSO-d₆) δ 12.11 (s, 1H), 7.72 (d, J=1.5 Hz, 1H), 7.50 (d,J=1.5 Hz, 1H), 7.42-7.28 (m, 5H), 5.13 (s, 2H), 2.35 (s, 3H), 2.15 (s,3H); ESI m/z 365 [M+H]⁺.

Step 4: To a solution of Example Compound 15 (52 mg, 0.14 mmol) in THF(5 mL) and water (4 mL) was added Na₂S₂O₄ (149 mg, 0.86 mmol). Themixture was stirred at rt for 4 h, 2N HCl (1 mL) was added, the mixturewas heated to reflux for 15 minutes then cooled to rt. Na₂CO₃ was addedslowly to adjust to pH 9. The mixture was extracted with CH₂Cl₂ (100mL), the organic layer was washed with brine (50 mL), filtered,concentrated and purified by chromatography (silica gel, 70-100% ethylacetate/hexanes) to afford Example Compound 16 (30 mg, 63%) as anoff-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 10.44 (s, 1H), 7.36-7.25(m, 5H), 6.28 (s, 2H), 5.04 (s, 2H), 4.95 (s, 2H), 2.28 (s, 3H), 2.10(s, 3H); ESI m/z 335 [M+H]⁺.

General Procedure H Preparation of4-(1-benzyl-4-bromo-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole(Example Compound 121)

Step 1: To a solution of 30 (1.09 g, 3.49 mmol) in tetrahydrofuran (30mL) was added sodium dithionite (4.86 g, 28.0 mmol) in water (15 mL).The reaction mixture was stirred at room temperature overnight andconcentrated under vacuum. The residue was dissolved in MeOH/water (1:1,150 mL) and the solid was precipitated by removing some MeOH undervacuum. The solid was filtered, washed with water and dried under vacuumto afford 37 (440 mg, 34%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ6.85 (d, J=1.8 Hz, 1H), 6.51 (d, J=1.8 Hz, 1H), 4.00-3.60 (bs, 2H),3.60-3.30 (bs, 2H), 2.36 (s, 3H), 2.23 (s, 3H); ESI m/z 282 [M+H]⁺.

Step 2: To a solution of 37 (4.01 g, 14.2 mmol) in methanol (87 mL) wasadded triethyl orthoacetate (3.45 g, 21.3 mmol) and sulfamic acid (69mg, 0.71 mmol). The reaction was stirred at room temperature for 5 h.The reaction mixture was diluted with water (50 mL), basified withNaHCO₃ and filtered. The solid was dried to afford 38 (4.2 g, 96%) as abrown solid: ¹H NMR (300 MHz, DMSO-d₆) δ 12.82 (br.s, 1H), 7.42 (d,J=1.5 Hz, 1H), 7.31 (d, J=1.5 Hz, 1H), 2.52 (s, 3H), 2.40 (s, 3H), 2.24(s, 3H).

Step 3: The mixture of 38 (300 mg, 0.980 mmol), benzyl bromide (503 mg,2.94 mmol), and potassium carbonate (676 mg, 4.90 mmol) in acetonitrile(50 mL) was heated in sealed tube at 75° C. overnight. The reactionmixture was cooled to room temperature, concentrated and purified bychromatography (silica gel, 0-100% ethyl acetate in hexanes) to giveExample Compound 121 (276 mg, 71%) as an off-white solid: ¹H NMR (500MHz, CD₃OD) δ 7.40-7.25 (m, 5H), 7.15 (d, J=7.7 Hz, 2H), 5.51 (s, 2H),2.64 (s, 3H), 2.32 (s, 3H), 2.15 (s, 3H); ESI m/z 396 [M+H]⁺.

Preparation of4-(1-benzyl-4-methoxy-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole(Example Compound 66)

A mixture of Example 121 (80 mg, 0.20 mmol), NaOCH₃ (108 mg, 2.0 mmol)and CuI (57 mg, 0.30 mmol) in MeOH (1 mL) and DMF (3 mL) was purged withnitrogen and heated at 100° C. for 6 h. The mixture was diluted withethyl acetate (100 mL) and washed with brine (50 mL). The organic layerwas dried over Na₂SO₄, filtered and concentrated. The residue waspurified by chromatography (silica gel, 40-100% EtOAc/hexanes) to affordExample Compound 66 (386 mg, 55%) as an off-white solid: ¹H NMR (300MHz, CDCl₃) δ 7.35-7.30 (m, 3H), 7.09-7.06 (m, 2H), 6.64 (d, J=1.2 Hz,1H), 6.53 (s, 1H), 5.32 (s, 2H), 4.03 (s, 3H), 2.66 (s, 3H), 2.33 (s,3H), 2.19 (s, 3H); ESI m/z 348 [M+H]⁺.

General Procedure I Preparation of1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-4-nitro-1H-benzo[d]imidazol-2-amine(Example Compound 18) and1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N²-ethyl-1H-benzo[d]imidazole-2,4-diamine(Example Compound 19)

Step 1: A mixture of Example Compound 15 (73 mg, 0.668 mmol) in POCl₃ (3mL) was heated at 110° C. for 16 h. The reaction mixture wasconcentrated, the residue was dissolved in CH₂Cl₂ (100 mL), washed withsaturated NaHCO₃ (2×50 mL) and brine (50 mL). The organic layer wasdried over sodium sulfate, filtered and concentrated. The residue wasdissolved in a solution of ethylamine in THF (2.0 M, 10 mL), and themixture was heated at 70° C. for 3 h. The reaction mixture wasconcentrated, the residue was purified by chromatography (silica gel,20-60% EtOAc/hexanes) to afford Example Compound 18 (113 mg, 43%) as anorange solid: ¹H NMR (300 MHz, CDCl₃) δ 7.84 (d, J=1.5 Hz, 1H),7.42-7.35 (m, 3H), 7.16-7.13 (m, 2H), 7.03 (d, J=1.5 Hz, 1H), 5.15 (s,2H), 4.29 (t, J=5.4 Hz, 1H), 3.78-3.69 (m, 2H), 2.36 (s, 3H), 2.21 (s,3H), 1.27 (t, J=7.5 Hz, 3H); ESI m/z 392 [M+H]⁺.

Step 2: To a solution of Example Compound 18 (90 mg, 0.23 mmol) in THF(5 mL) and water (4 mL) was added Na₂S₂O₄ (240 mg, 1.38 mmol). Themixture was stirred at rt for 4 h, 2N HCl (1 mL) was added, the mixturewas heated to reflux for 15 minutes then cooled to rt. Na₂CO₃ was addedslowly to adjust to pH 9. The mixture was extracted with CH₂Cl₂ (100mL), the organic layer was washed with brine (50 mL), dried over Na₂SO₄,filtered, concentrated and purified by chromatography (silica gel, 0-10%methanol/ethyl acetate) to afford Example Compound 19 (60 mg, 72%) as anoff-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.34-7.20 (m, 5H), 6.62 (t,J=5.4 Hz, 1H), 6.30 (d, J=1.5 Hz, 1H), 6.21 (d, J=1.5 Hz, 1H), 5.19 (s,2H), 4.83 (s, 2H), 3.47-3.38 (m, 2H), 2.28 (s, 3H), 2.11 (s, 3H), 1.22(t, J=7.2 Hz, 3H); ESI m/z 362 [M+H]⁺.

General Procedure J Preparation of methyl1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate(Example Compound 20),1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxamide(Example Compound 21) and4-(aminomethyl)-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one(Example Compound 22)

Step 1: To a solution of 39 (2.00 g, 8.70 mmol) in 1,4-dioxane (80 mL)and water (8, mL) was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(2.13 g, 9.57 mmol), potassium carbonate (2.40 g, 17.4 mmol) andtetrakis(triphenylphosphine)palladium(0) (502 mg, 0.435 mmol). Thereaction mixture was purged with nitrogen and heated at 90° C.overnight. The reaction mixture was cooled to room temperature,concentrated and purified by chromatography (silica gel, 0-50% ethylacetate in hexanes) to afford 40 (1.43 g, 63%) as an off-white solid: ¹HNMR (500 MHz, CDCl₃) δ 7.74 (d, J=2.1 Hz, 1H), 7.15 (dd, J=2.1, 8.4 Hz,1H), 6.73 (d, J=8.4 Hz, 1H), 5.81 (s, 2H), 3.88 (s, 3H), 2.37 (s, 3H),2.23 (s, 3H); ESI m/z 247 [M+H]⁺.

Step 2: To a mixture of 40 (1.34 g, 5.45 mmol) in acetic acid (40 mL)was added N-bromosuccinimide (1.07 g, 5.99 mmol). The mixture wasstirred at room temperature for 30 min and concentrated. The residue wasdissolved in MeOH and neutralized to pH 7 with 10% sodium bicarbonate.The mixture was diluted with water, filtered. The filter cake was washedwith water, and dried under vacuum to afford 41 (1.65 g, 93%) as ayellow solid: ¹H NMR (500 MHz, CDCl₃) δ 7.74 (d, J=2.1 Hz, 1H), 7.47 (d,J=2.1 Hz, 1H), 6.43 (bs, 2H), 3.90 (s, 3H), 2.37 (s, 3H), 2.23 (s, 3H).

Step 3: To a solution of 41 (500 mg, 1.54 mmol) in toluene (40 mL) undernitrogen atmosphere was added benzylamine (823 mg, 7.69 mmol), cesiumcarbonate (1.00 g, 2.08 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (110 mg,0.231 mmol), and tris(dibenzylideneacetone) dipalladium(O) (141 mg,0.154 mmol). The reaction mixture was heated at 90° C. overnight, cooledto room temperature and purified by chromatography (silica gel, 0-20%ethyl acetate in hexanes) to afford 42 (310 mg, 57%) as a light brownsolid: ¹H NMR (500 MHz, CDCl₃) δ 7.40-7.25 (m, 6H), 6.56 (d, J=1.8 Hz,1H), 5.68 (s, 2H), 4.36 (d, J=4.4 Hz, 2H), 3.88 (s, 3H), 3.68 (s, 1H),2.22 (s, 3H), 2.09 (s, 3H); ESI m/z 352 [M+H]⁺.

Step 4: To a mixture of 42 (310 mg, 0.883 mmol) in 1,4-dioxane (10 mL)was added 1,1′-carbonyldiimidazole (244 mg, 2.12 mmol) and DMAP (onecrystal). The reaction was heated in a sealed tube at 80° C. for 5 days.The mixture was concentrated and purified by chromatography (silica gel,0-100% ethyl acetate in hexanes) to give Example Compound 20 (160 mg,48%) as an off-white solid: ¹H NMR (500 MHz, CD₃OD) δ 7.54 (d, J=1.5 Hz,1H), 7.37-7.24 (m, 5H), 7.07 (d, J=1.5 Hz, 1H), 5.14 (s, 2H), 3.97 (s,3H), 2.27 (s, 3H), 2.09 (s, 3H); HPLC>99%, t_(R)=15.0 min; ESI m/z 378[M+H]⁺.

Step 5: To a mixture of Example Compound 20 (50 mg, 0.13 mmol) informamide (4 mL) was added potassium tert-butoxide (30 mg, 0.26 mmol).The mixture was heated in the microwave at 100° C. for 3 h,concentrated, and purified by chromatography (silica gel, 0-20% methanolin ethyl acetate) to afford Example Compound 21 (13 mg, 26%) as anoff-white solid: ¹H NMR (500 MHz, CD₃OD) δ 7.41 (d, J=1.3 Hz, 1H),7.37-7.24 (m, 5H), 7.00 (d, J=1.4 Hz, 1H), 5.13 (s, 2H), 2.28 (s, 3H),2.11 (s, 3H); HPLC 98.3%, t_(R)=12.3 min; ESI m/z 363 [M+H]⁺.

Step 6: To a solution of Example Compound 21 (40 mg, 0.11 mmol) in THF(10 mL) under nitrogen atmosphere was added sodium borohydride (38 mg,0.99 mmol). The mixture was heated to 65° C. and boron trifluoridediethyl etherate (0.2 mL) was added. The mixture was heated at 65° C.for 2 h. After cooling to room temperature, hydrochloride acid (2N, 5mL) was added and the mixture stirred for 2 h. The mixture was basifiedwith NaOH (2N, 5 mL), concentrated, and purified by chromatography(silica gel, 0-100% CMA in methylene chloride)(CMA=chloroform:methanol:concentrated ammonium hydroxide=80:18:2). Itwas further purified by reverse phase HPLC on a Polaris column elutingwith 10-90% CH₃CN in H₂O to give Example Compound 22 (16 mg, 42%) as anoff-white solid: ¹H NMR (500 MHz, CD₃OD) δ 7.37-7.23 (m, 5H), 6.99 (d,J=1.4 Hz, 1H), 6.77 (d, J=1.4 Hz, 1H), 5.10 (s, 2H), 3.93 (s, 2H), 2.27(s, 3H), 2.10 (s, 3H); ESI m/z 340 [M+H]⁺.

General Procedure K1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-amine(Example Compound 55)

A mixture of Example 121 (250 mg, 0.63 mmol), BocNH₂ (221 mg, 1.89mmol), Xantphos (73 mg, 0.126 mmol), Pd₂(dba)₃ (58 mg, 0.063 mmol) andCs₂CO₃ (720 mg, 2.21 mmol) in 1,4-dioxane (13 mL) was purged withnitrogen and heated at 100° C. for 18 h. The mixture was diluted withmethylene chloride (200 mL) and filtered. The filtrate was concentratedand purified by chromatography (silica gel, 0-50% EtOAc/hexanes) toafford a light brown foam which was dissolved in CH₂Cl₂ (4 mL), TFA (2mL) was added. The mixture was stirred at rt for 2 h, concentrated, theresidue was dissolved in ethyl acetate (100 mL) and washed withsaturated NaHCO₃ (50 mL×2). The organic layer was dried over sodiumsulfate, filtered and concentrated. Purification by chromatography(silica gel, 0-10% MeOH/EtOAc) afforded Example Compound 55 (146 mg,88%) as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ 7.34-7.28 (m, 3H),7.09-7.08 (m, 2H), 6.42 (d, J=1.5 Hz, 1H), 6.36 (d, J=1.5 Hz, 1H), 5.28(s, 2H), 4.42 (br.s, 2H), 2.60 (s, 3H), 2.31 (s, 3H), 2.17 (s, 3H); ESIm/z 333 [M+H]⁺.

Preparation of1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carbonitrile(Example Compound 88) and4-(1-benzyl-3-chloro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole(Example Compound 89)

Step 1: To a suspension of 43 (200 mg, 1.0 mmol) in CH₃CN (6 mL) wasadded ClSO₂NCO (360 mg, 2.5 mmol). The reaction mixture was stirred at60° C. for 4 h. After the mixture was cooled to rt, DMF (1 mL) wasadded. The mixture was stirred at rt for 1 h. The mixture was dilutedwith 30% i-PrOH in CHCl₃ (50 mL) and washed with brine (20 mL). Theorganic layer was dried over sodium sulfate, filtered and concentrated.The crude was dissolved in CH₃CN (4 mL), potassium carbonate (280 mg,2.0 mmol) and benzyl chloride (128 mg, 1.0 mmol) were added. Thereaction was stirred at 70° C. for 16 h. The reaction mixture wasfiltered through a layer of celite, concentrated. The residue waspurified by chromatography (silica gel, 0-50% ethyl acetate/hexanes) toafford 44 (16 mg, 5%) as a yellow oil and 45 (12 mg, 4%) as an off-whitesolid; 44: ESI MS m/z 312 [M+H]⁺; 45: ESI MS m/z 321 [M+H]⁺.

Step 2: Using the similar procedure used for General Procedure C step 1on compound 44 (16 mg, 0.051 mmol) afforded Example Compound 88 (6 mg,36%) as an off-white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.55 (s, 1H), 7.98(s, 1H), 7.50 (s, 1H), 7.41-7.40 (m, 3H), 7.20-7.15 (m, 2H), 5.42 (s,2H), 2.34 (s, 3H), 2.16 (s, 3H); ESI MS m/z 329 [M+H]⁺.

Using the similar procedure used for General Procedure C step 1 oncompound 45 (12 mg, 0.037 mmol) afforded Example Compound 89 (8 mg, 64%)as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 8.49 (s, 1H), 7.55 (s, 1H),7.50 (s, 1H), 7.38-7.36 (m, 3H), 7.18-7.16 (m, 2H), 5.36 (s, 2H), 2.34(s, 3H), 2.16 (s, 3H); ESI MS m/z 338 [M+H]⁺.

General Procedure M Preparation of5-(3,5-dimethylisoxazol-4-yl)-N-phenyl-1H-pyrrolo[3,2-b]pyridin-3-amine(Example Compound 23)

Step 1: To a solution of 46 (500 mg, 2.54 mmol) in 1,4-dioxane (10 mL)was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(792 mg, 3.56 mmol), sodium carbonate (538 mg in 2 mL H₂O, 5.08 mmol)and tetrakis(triphenylphosphine)palladium(0) (294 mg, 0.25 mmol). Thereaction mixture was purged with nitrogen and heated at 90° C. for 16 h.The mixture was filtered through a layer of Celite. The filtrate wasconcentrated. Purification by chromatography (silica gel, 0-50% ethylacetate/dichloromethane) afforded 47 (700 mg, >100%) as a yellow oil: ¹HNMR (300 MHz, DMSO-d₆) δ 11.4 (s, 1H), 7.85 (dd, J=8.1, 0.9 Hz, 1H),7.68 (t, J=3.0 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H), 6.58 (d, J=2.1 Hz, 1H),2.49 (s, 3H), 2.37 (s, 3H).

Step 2: To a solution of 47 (700 mg, 2.54 mmol) in DMF (8 mL) at 0° C.was added NBS (497 mg, 2.79 mmol). The reaction mixture was stirred at0° C. for 2 h. The mixture was diluted with methylene chloride (50 mL)and washed with brine (20 mL). The organic layer was dried over sodiumsulfate, filtered and concentrated. Purification by chromatography(silica gel, 0-50% ethyl acetate/dichloromethane) afforded 48 (660 mg,89%) as a brown solid: ¹H NMR (300 MHz, DMSO-ds) δ 11.8 (s, 1H), 7.92(d, J=6.0 Hz, 1H), 7.90 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 2.49 (s, 3H),2.37 (s, 3H); ESI m/z 292 [M+H]⁺.

Step 3: To a solution of 48 (250 mg, 0.86 mmol) in CH₂Cl₂ (5 mL) wasadded NEt₃ (130 mg, 1.28 mmol), DMAP (12 mg, 0.1 mmol) and di-tert-butyldicarbonate (224 mg, 1.03 mmol). The reaction was stirred at rt for 16h. The reaction mixture was concentrated. Purification by chromatography(silica gel, 0-30% ethyl acetate/hexanes) afforded 49 (210 mg, 70%) asan off-white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.43 (d, J=5.4 Hz, 1H),7.93 (s, 1H), 7.34 (d, J=5.1 Hz, 1H), 2.64 (s, 3H), 2.50 (s, 3H), 1.69(s, 9H).

Step 4: To a solution of 49 (100 mg, 0.26 mmol) in 1,4-dioxane (5 mL)under nitrogen atmosphere was added aniline (71 mg, 0.76 mmol), cesiumcarbonate (250 mg, 0.76 mmol), X-phos (24 mg, 0.05 mmol), andtris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.03 mmol). Thereaction mixture was heated at 90° C. for 16 h. The mixture was dilutedwith methylene chloride (10 mL) and filtered through a layer of Celite.The filtrate was concentrated. Purification by chromatography (silicagel, 0-50% ethyl acetate/hexanes) gave a red oil which was dissolved inmethylene chloride (5 mL), TFA (2 mL) was added, the mixture was stirredat rt for 2 h. The mixture was concentrated, the residue was dissolvedin methylene chloride (100 mL), washed with saturated NaHCO₃ (50 mL×2)and brine (50 mL). The organic layer was dried over sodium sulfate,filtered and concentrated. Purification by chromatography (silica gel,0-50% ethyl acetate/dichloromethane) afforded Example Compound 23 (47mg, 64%) as a yellow solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.1 (d, J=1.8Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.61 (d, J=2.7 Hz, 1H), 7.43 (s, 1H),7.25 (d, J=8.4 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 7.07 (d, J=7.2 Hz, 1H),6.85 (d, J=7.5 Hz, 2H), 6.60 (t, J=7.2 Hz, 1H), 2.48 (s, 3H), 2.29 (s,3H); ESI MS m/z 305 [M+H]⁺.

General Procedure N Preparation of6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine-4-oxide(Example Compound 24) and6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-5(4H)-one(Example Compound 25)

Step 1: To a solution of Example Compound 53 (85 mg, 0.25 mmol) inCH₂Cl₂ (3 mL) was added m-CPBA (160 mg, 0.5 mmol). The reaction mixturewas stirred at rt for 7 h. The mixture was diluted with methylenechloride (50 mL) and washed with 10% Na₂S₂O₃ solution (10 mL), 2N NaOHsolution (10 mL) and brine (10 mL). The organic layer was dried oversodium sulfate, filtered and concentrated. Purification bychromatography (silica gel, 0-70% ethyl acetate/dichloromethane)afforded Example Compound 24 (60 mg, 67%) as an off-white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 8.21 (d, J=0.9 Hz, 1H), 7.83 (d, J=0.9 Hz, 1H),7.40-7.35 (m, 2H), 7.20-7.14 (m, 2H), 5.59 (s, 2H), 2.69 (s, 3H), 2.45(s, 3H), 2.27 (s, 3H); ESI MS m/z 353 [M+H]⁺.

Step 2: A solution of Example Compound 24 (32 mg, 0.091 mmol) in Ac₂O (3mL) was heated at 130° C. for 2 h. The mixture was concentrated. Theresidue was diluted with 1:1 CH₃OH/H₂O (10 mL) and stirred at 80° C. for10 h. The reaction mixture was concentrated. Purification bychromatography (silica gel, 0-5% methanol/dichloromethane) affordedExample Compound 25 (20 mg, 63%) as an off-white solid: ¹H NMR (300 MHz,DMSO-d₆) δ 12.0 (s, 1H), 8.07 (s, 1H), 7.36-7.31 (m, 2H), 7.19-7.13 (m,2H), 5.45 (s, 2H), 2.30 (s, 6H), 2.14 (s, 3H); ESI MS m/z 353 [M+H]⁺.

Preparation of4-(3-benzyl-3H-imidazo[4,5-b]pyridin-5-yl)-3,5-dimethylisoxazole(Example Compound 26)

Step 1: To a solution of 50 (560 mg, 2.57 mmol) in CH₃CN (15 mL) wasadded K₂CO₃ (887 mg, 6.43 mmol) and benzyl chloride (484 mg, 2.83 mmol).The reaction was heated at 60° C. for 16 h. The mixture was diluted withethyl acetate (100 mL), filtered and concentrated to give 51 (790 mg,100%) as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 8.58 (brs, 1H), 8.24(d, J=8.4 Hz, 1H), 7.46-7.35 (m, 5H), 6.82 (d, J=8.7 Hz, 1H), 4.82 (d,J=5.7 Hz, 2H).

Step 2: To a solution of 51 (790 mg, 2.56 mmol) in 1,4-dioxane (25 mL)was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(1.14 g, 5.12 mmol), sodium carbonate (2.0 M in H₂O, 3.84 mL, 7.68 mmol)and tetrakis(triphenylphosphine)palladium(0) (300 mg, 0.26 mmol). Thereaction mixture was purged with nitrogen and heated at 90° C. for 8 h.The mixture was diluted with methylene chloride (200 mL) and filtered.The filtrate was concentrated and purified by chromatography (silicagel, 0-20% EtOAc/hexanes) to afford 52 (500 mg, 60%) as a yellow oil: ¹HNMR (300 MHz, DMSO-d₆) δ 9.09 (t, J=6.0 Hz, 1H), 8.51 (d, J=8.4 Hz, 1H),7.32-7.20 (m, 5H), 6.96 (d, J=8.7 Hz, 1H), 4.85 (d, J=6.3 Hz, 2H), 2.47(s, 3H), 2.25 (s, 3H); ESI m/z 325 [M+H]⁺.

Step 3: To a solution of 52 (500 mg, 1.54 mmol) in THF (15 mL) and water(12 mL) was added Na₂S₂O₄ (1.61 g, 9.24 mmol). The mixture was stirredat rt for 5 h; 2 N HCl (10 mL) was added, and the mixture was heated toreflux for 15 minutes then cooled to rt. Na₂CO₃ was added slowly toadjust to pH 9. The mixture was extracted with ethyl acetate (100 mL),the organic layer was washed with brine (50 mL), filtered andconcentrated to give 53 (460 mg, 100%) as a brown oil: ¹H NMR (300 MHz,DMSO-d₆) δ 7.33-7.18 (m, 5H), 6.78 (d, J=7.5 Hz, 1H), 6.52 (d, J=7.5 Hz,1H), 6.29 (t, J=5.7 Hz, 1H), 4.94 (s, 2H), 4.60 (d, J=5.7 Hz, 2H), 2.36(s, 3H), 2.17 (s, 3H); ESI m/z 295 [M+H]⁺.

Step 4: A solution of 53 (150 mg, 0.51 mmol), trimethylorthoformate (81mg, 0.765 mmol) and sulfamic acid (3 mg) in MeOH (5 mL) was heated toreflux for 4 h. The mixture was concentrated, the residue was purifiedby chromatography (silica gel, 30-100% ethyl acetate/hexanes) to affordExample Compound 26 (100 mg, 65%) as an off-white solid: ¹H NMR (300MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.17 (d, J=8.1 Hz, 1H), 7.44 (d, J=8.1 Hz,1H), 7.36-7.27 (m, 5H), 5.52 (s, 2H), 2.54 (s, 3H), 2.34 (s, 3H); ESIm/z 305 [M+H]⁺.

Preparation of6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-1H-benzo[d]imidazol-4-amine(Example Compound 27),6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-N-methyl-1H-benzo[d]imidazol-4-amine(Example Compound 28) and6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-N,N-dimethyl-1H-benzo[d]imidazol-4-amine(Example Compound 29)

Example Compound 27 was made followed by the similar procedure describedfor Example 7: ¹H NMR (300 MHz, DMSO-d₆) δ 8.23 (s, 1H), 7.42 (dd,J=8.0, 6.0 Hz, 2H), 7.17 (dd, J=9.0, 9.0 Hz, 2H), 6.62 (s, 1H), 6.32 (s,1H), 5.40 (s, 4H), 2.33 (s, 3H), 2.16 (s, 3H); ESI m/z 337 [M+H]⁺.

To a solution of Example Compound 27 (35 mg, 0.10 mmol) in methylenechloride (5 mL), was added a 37% solution of formaldehyde in water (8.5μL) and acetic acid (1 drop). The solution was stirred for 45 min,sodium triacetoxyborohydride (66 mg, 0.31 mmol) was added and themixture stirred for 16 h. The mixture was diluted with methylenechloride (20 mL) and neutralized with saturated sodium bicarbonate (5mL). The organic layer was dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified by chromatography(silica gel, 0-75% ethyl acetate/methylene chloride) to afford ExampleCompound 28 as a white solid (8 mg, 22%) and Example Compound 29 as aclear solid (7 mg, 18%). Example Compound 28: ¹H NMR (500 MHz, DMSO-d₆)δ 8.22 (s, 1H), 7.43 (dd, J=8.8, 5.5 Hz, 2H), 7.16 (dd, J=8.8, 5.5 Hz,2H), 6.65 (d, J=1.0 Hz, 1H), 6.09 (d, J=1.0 Hz, 1H), 5.85 (q, J=5.0 Hz,1H), 5.41 (s, 2H), 2.83 (d, J=5.5 Hz, 3H), 2.35 (s, 3H), 2.17 (s, 3H);ESI m/z 351 [M+H]⁺; Example 29: ¹H NMR (500 MHz, DMSO-d₆) δ 8.28 (s,1H), 7.41 (dd, J=8.5, 5.5 Hz, 2H), 7.17 (dd, J=9.0, 9.0 Hz, 2H), 6.85(d, J=1.0 Hz, 1H), 6.25 (d, J=1.0 Hz, 1H), 5.43 (s, 2H), 3.18 (s, 6H),2.35 (s, 3H), 2.18 (s, 3H); ESI m/z 365 [M+H]⁺.

Preparation of4-(1-benzyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole(Example Compound 30)

Step 1: To a suspension of 3-amino-5-bromo-2-nitropyridine (54, 780 mg,3.58 mmol) and potassium carbonate (2.28 g, 16.5 mmol) in dryacetonitrile (50 mL) was added 1-(bromoethyl)benzene (1.22 g, 6.60mmol). The mixture was heated to 80° C. for 48 h then water (20 mL) andethyl acetate (20 mL) were added. The layers were separated and theaqueous layer was extracted with ethyl acetate (2×20 mL). The combinedethyl acetate fractions were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by chromatography (silica gel,0-40% ethyl acetate in hexanes) to afford 55 (219 mg, 19%) as a yellowsolid: ¹H NMR (500 MHz, CDCl₃) δ 8.14 (d, J=5.0 Hz, 1H), 7.84 (d, J=2.0Hz, 1H), 7.40-7.29 (m, 6H), 4.64 (quint, J=6.5 Hz, 1H), 1.67 (d, J=7.0Hz, 3H).

Step 2: To a mixture of 55 (261 mg, 0.81 mmol) and 3 (217 mg, 0.97 mmol)in 1,4-dioxane (7 mL) and water (1.5 mL) was added potassium carbonate(224 mg, 1.62 mmol) and tetrakis(triphenylphosphine)palladium(0) (47 mg,0.04 mmol). The reaction was stirred and heated at 90° C. for 17 h. Thereaction mixture was diluted with methanol (20 mL) and silica gel (15 g)was added. The suspension was concentrated to dryness and the resultingpowder was loaded onto silica gel and eluted with 0-50% ethyl acetate inhexanes. The clean product was concentrated to give 56 (226 mg, 82%) asa yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 8.19 (d, J=4.5 Hz, 1H), 7.77(d, J=2.0 Hz, 1H), 7.40-7.28 (m, 5H), 6.89 (d, J=2.0 Hz, 1H), 4.66(quint, J=5.0 Hz, 1H), 2.10 (s, 3H), 1.94 (s, 3H), 1.71 (d, J=7.0 Hz,3H).

Step 3: To a solution of 56 (226 mg, 0.67 mmol) in THF (20 ml) was addeda solution of sodium dithionite (698 mg, 4.01 mmol) in water (20 mL)dropwise over 5 min. The solution was stirred at room temperature for 16h and the solvents were removed in vacuo. Methanol (20 mL) was added andthe suspension stirred at room temperature for 3 h. The mixture wasfiltered and the filtrate was concentrated to dryness. A solution of 2Naq. HCl was added to the residue and was heated to reflux for 5 min.After concentration to dryness, methanol was added (10 mL) and thesolution was adjusted to pH 8 using saturated aq. NaHCO₃ solution (20mL). Silica gel was added (10 g) and the suspension was concentrated todryness. The resulting powder was loaded onto silica gel and eluted with0-70% ethyl acetate in hexanes. The clean product was concentrated togive 57 (96 mg, 47%) as a beige solid: ¹H NMR (500 MHz, CDCl₃) δ 7.42(d, J=2.0 Hz, 1H), 7.33-7.30 (m, 4H), 7.25-7.22 (m, 1H), 6.34 (d, J=1.5Hz, 1H), 4.44 (quint, J=5.0 Hz, 1H), 4.36 (br s, 2H), 3.70 (br s, 1H),2.07 (s, 3H), 1.89 (s, 3H), 1.58 (d, J=6.5 Hz, 3H).

Step 4: A mixture of 57 (47 mg, 0.15 mmol), trimethylorthoformate (2 mL,18.3 mmol) and sulfamic acid (1 mg) were heated in a sealed tube at 100°C. for 30 min. The mixture was cooled, concentrated and loaded ontosilica gel and eluted with 0-20% ethyl acetate in hexanes. The resultingmaterial was purified by reverse phase HPLC on a Polaris column elutingwith 10-90% CH₃CN in H₂O to afford (Example Compound 30) (19 mg, 39%) asa white solid: ¹H NMR (500 MHz, CD₃OD) δ 8.76 (s, 1H), 8.36 (d, J=2.0Hz, 1H), 7.65 (d, J=2.5 Hz, 1H), 7.40-7.30 (m, 5H), 4.44 (q, J=7.0 Hz,1H), 2.29 (s, 3H), 2.10 (s, 3H), 2.06 (d, J=7.0 Hz, 3H). ESI m/z 319[M+H]⁺.

Preparation of4-(1-benzyl-1H-imidazo[4,5-c]pyridin-6-yl)-3,5-dimethylisoxazole(Example Compound 31),1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-c]pyridine 5-oxide(Example 32) and1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-c]pyridin-4-amine(Example Compound 33)

Step 1: To a solution of 58 (1.00 g, 5.76 mmol) in 1,4-dioxane (40 mL)and water (4 mL) was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(1.93 g, 8.64 mmol), potassium carbonate (1.59 g, 11.5 mmol), andtetrakis(triphenylphosphine)palladium(0) (333 mg, 0.288 mmol). Thereaction mixture was purged with nitrogen and heated at 90° C.overnight. The reaction mixture was cooled to room temperature,concentrated and purified by chromatography (silica gel, 0-100% ethylacetate in hexanes) to afford 59 (1.42 g, >99%) as a yellow solid: ¹HNMR (300 MHz, CDCl₃) δ 9.26 (s, 1H), 6.67 (s, 1H), 6.90-6.00 (bs, 2H),2.61 (s, 3H), 2.44 (s, 3H); ESI m/z 235 [M+H]⁺.

Step 2: A mixture of 59 (710 mg, 3.03 mmol), benzyl bromide (778 mg,4.55 mmol), and potassium carbonate (836 mg, 6.06 mmol) in acetonitrile(30 mL) was heated in sealed tube at 90° C. overnight. The reactionmixture was cooled to room temperature, concentrated and purified bychromatography (silica gel, 0-30% ethyl acetate in hexanes) to afford 60(303 mg, 30%) as a brown solid: ¹H NMR (500 MHz, CDCl₃) δ 9.26 (s, 1H),8.68 (s, 1H), 7.50-7.10 (m, 5H), 6.50 (s, 1H), 4.65 (d, J=4.1 Hz, 2H),2.39 (s, 3H), 2.19 (s, 3H); ESI m/z 325 [M+H]⁺.

Step 3: To a solution of 60 (300 mg, 0.926 mmol) in tetrahydrofuran (10mL) was added sodium dithionite (967 mg, 5.56 mmol) in water (10 mL).The reaction mixture was stirred at room temperature overnight andconcentrated under vacuum. The residue was suspended in MeOH and thesolid was filtered, washed with MeOH, and the filtrate concentratedunder vacuum. To the residue was added 2N HCl and heated to justboiling, cooled to room temperature and concentrated under vacuum. Theresidue was dissolved in MeOH and basified with 10% NaHCO₃, concentratedand purified by chromatography (silica gel, 0-20% methanol in ethylacetate) to afford 61 (150 mg, 55%) as a gray solid: ¹H NMR (500 MHz,CDCl₃) δ 7.99 (s, 1H), 7.40-7.28 (m, 5H), 6.39 (s, 1H), 4.64 (s, 1H),4.43 (d, J=5.4 Hz, 2H), 3.15 (s, 2H), 2.33 (s, 3H), 2.21 (s, 3H); ESIm/z 295 [M+H]⁺.

Step 4: To a solution of 61 (150 mg, 0.51 mmol) in ethanol (5 mL) wasadded trimethylorthoformate (81 mg, 0.77 mmol) and sulfamic acid (1 mg,0.01 mmol). The reaction was heated in a sealed tube at 90° C.overnight. The mixture was concentrated and purified by chromatography(silica gel, 0-100% ethyl acetate in hexanes) to give Example Compound31 (143 mg, 92%) as a yellow solid: ¹H NMR (500 MHz, CD₃OD) δ 9.00 (d,J=1.0 Hz, 1H), 8.05 (s, 1H), 7.48 (d, J=1.0 Hz, 1H), 7.40-7.30 (m, 5H),5.58 (s, 2H), 2.40 (s, 3H), 2.25 (s, 3H); ESI m/z 305 [M+H]⁺.

Step 5: To a mixture of Example Compound 31 (100 mg, 0.329 mmol) indichloromethane (5 mL) was added 3-chloroperoxybenzoic acid (264 mg, 77%with water, 1.18 mmol). The mixture was stirred at room temperatureovernight, concentrated and purified by chromatography (silica gel,0-20% methanol in ethyl acetate) to afford Example Compound 32 (127mg, >99%) as an off-white solid: ¹H NMR (500 MHz, CD₃OD) δ 8.92 (s, 1H),8.61 (s, 1H), 7.67 (s, 1H), 7.45-7.25 (m, 5H), 6.57 (s, 2H), 2.28 (s,3H), 2.17 (s, 3H); ESI m/z 321 [M+H]⁺.

Step 6: To a mixture of phosphorus oxybromide (268 mg, 0.938 mmol) inDMF (2 mL) was added Example 32 (100 mg, 0.313 mmol) in DMF (6 mL). Themixture was stirred at room temperature for 10 min and heated at 100° C.for 1 h. After cooling to room temperature, water and MeOH were added.The mixture was neutralized to pH 7 by addition of 10% sodiumbicarbonate and concentrated. The residue was purified by chromatography(silica gel, 0-100% ethyl acetate in hexanes) to afford 62 (30 mg, 25%)as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.09 (s, 1H), 7.43-7.35(m, 3H), 7.23-7.19 (m, 2H), 7.03 (s, 1H), 5.38 (s, 2H), 2.47 (s, 3H),2.31 (s, 3H); ESI m/z 383 [M+H]⁺.

Step 7: To a solution of 62 (30 mg, 0.078 mmol) in toluene (10 mL) undernitrogen atmosphere was added tert-butyl carbamate (27 mg, 0.23 mmol),cesium carbonate (51 mg, 0.16 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (6 mg, 0.01mmol) and tris(dibenzylideneacetone) dipalladium(O) (7 mg, 0.008 mmol).The reaction mixture was heated at 90° C. overnight, cooled to roomtemperature, and purified by chromatography (silica gel, 0-20% methanolin ethyl acetate). It was further purified by reverse phase HPLC on aPolaris column eluting with 10-90% CH₃CN in H₂O to give Example Compound33 (10 mg, 40%) as an off-white solid: ¹H NMR (500 MHz, CD₃OD) δ 8.21(s, 1H), 7.42-7.25 (m, 5H), 6.70 (s, 1H), 5.46 (s, 2H), 2.39 (s, 3H),2.24 (s, 3H); HPLC 96.9%, t_(R)=10.1 min; ESI m/z 320 [M+H]⁺.

Preparation of4-(1-benzyl-3-bromo-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole.(Example Compound Compound 34)

Step 1: To a solution of 46 (1.0 g, 5.08 mmol) in 1,4-dioxane (50 mL)was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(1.47 g, 6.6 mmol), sodium carbonate (1.10 g in 8 mL H₂O, 10.2 mmol) andtetrakis(triphenylphosphine)palladium(0) (587 mg, 0.51 mmol). Thereaction mixture was purged with nitrogen and heated at 90° C. for 16 h.The mixture was filtered through a layer of Celite and the filtrate wasconcentrated. Purification by chromatography (silica gel, 0-50% ethylacetate/dichloromethane) afforded 63 (850 mg, 79%) as a yellow solid: ¹HNMR (300 MHz, DMSO-d₆) δ 11.4 (s, 1H), 8.30 (t, J=2.1 Hz, 1H), 7.75 (dd,J=1.8, 0.9 Hz, 1H), 7.70 (t, J=3.0 Hz, 1H), 6.61-6.59 (m, 1H), 2.42 (s,3H), 2.24 (s, 3H).

Step 2/3: To a solution of 63 (500 mg, 2.35 mmol) in DMF (10 mL) at 0°C. was added NBS (500 mg, 2.82 mmol). The reaction mixture was stirredat 0° C. for 2 h. The mixture was diluted with methylene chloride (50mL) and washed with brine (20 mL). The organic layer was dried oversodium sulfate, filtered and concentrated. The crude 64 was carriedforward. To a solution of 64 (300 mg, 1.03 mmol) in DMF (1 mL) and CH₃CN(10 mL) was added potassium carbonate (283 mg, 2.06 mmol) and benzylchloride (130 mg, 1.03 mmol). The reaction was stirred at 70° C. for 16h. The mixture was filtered through a layer of Celite and the filtratewas concentrated. Purification by chromatography silica gel, 0-50% ethylacetate/dichloromethane) afforded Example Compound 34 (200 mg, 51%) asan off-white solid: ¹H NMR (500 MHz, CD₃OD) δ 8.33 (d, J=1.5 Hz, 1H),7.86 (s, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.34-7.24 (m, 5H), 5.48 (s, 2H),2.35 (s, 3H), 2.17 (s, 3H); ESI MS m/z 382 [M+H]⁺.

Preparation of1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde(Example Compound 35)

Step 1: To a mixture of 46 (300 mg, 1.5 mmol) and hexamethylenetetramine(0.32 g, 2.25 mmol) was added AcOH (2 mL). The reaction mixture wasstirred at 120° C. for 6 h and was quenched with H₂O (5 mL). Theprecipitate was collected by filtration to afford 65 (190 mg, 56%) as ayellow solid: ¹H NMR (300 MHz, DMSO-d₆) δ 12.4 (s, 1H), 10.1 (s, 1H),8.58 (d, J=2.1 Hz, 1H), 8.47 (s, 1H), 8.18 (d, J=2.1 Hz, 1H).

Step 2: To a solution of 65 (190 mg, 0.84 mmol) in 1,4-dioxane (5 mL)was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(245 mg, 1.09 mmol), sodium carbonate (178 mg in 1 mL H₂O, 1.68 mmol)and tetrakis(triphenylphosphine)palladium(0) (97 mg, 0.08 mmol). Thereaction mixture was purged with nitrogen and heated at 90° C. for 16 h.The mixture was filtered through a layer of Celite and the filtrate wasconcentrated. Purification by chromatography (silica gel, 0-50% ethylacetate/dichloromethane) afforded 66 (135 mg, 67%) as an off-whitesolid: ¹H NMR (300 MHz, DMSO-d₆) δ 12.5 (s, 1H), 10.2 (s, 1H), 8.51 (d,J=1.8 Hz, 1H), 8.49 (d, J=3.0 Hz, 1H), 7.92 (d, J=1.8 Hz, 1H), 2.44 (s,3H), 2.26 (s, 3H); ESI MS m/z 242 [M+H]⁺.

Step 3: To a solution of 66 (92 mg, 0.38 mmol) in DMF (0.5 mL) and CH₃CN(5 mL) was added potassium carbonate (105 mg, 0.76 mmol) and benzylchloride (58 mg, 0.46 mmol). The reaction was stirred at 70° C. for 16h. The reaction mixture was filtered through a layer of Celite and thefiltrate was concentrated. Purification by chromatography (silica gel,0-50% ethyl acetate/dichloromethane) afforded Example Compound 35 (72mg, 57%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 10.2 (s,1H), 8.73 (s, 1H), 8.53 (d, J=1.8 Hz, 1H), 8.11 (d, J=1.8 Hz, 1H),7.44-7.30 (m, 5H), 5.59 (s, 2H), 2.40 (s, 3H), 2.21 (s, 3H); ESI MS m/z332 [M+H]⁺.

Preparation of1-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)-N,N-dimethylmethanamine(Example Compound 72)

A solution of Example Compound 35 (54 mg, 0.16 mmol), dimethylamine(0.25 mL, 2M in THF, 0.49 mmol) and NaBH(OAc)₃ (104 mg, 0.49 mmol) inCH₂Cl₂ (3 mL) was stirred at room temperature for 16 h. The reactionmixture was concentrated under reduced pressure. The crude reactionmixture was purified by chromatography (silica gel, 0-10%methanol/dichloromethane) to provide Example Compound 72 (42 mg, 71%) asan off-white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.34 (d, J=1.8 Hz, 1H),8.30 (s, 1H), 7.36-7.32 (m, 4H), 7.21-7.18 (m, 2H), 5.39 (s, 2H), 4.50(s, 2H), 2.86 (s, 6H), 2.32 (s, 3H), 2.16 (s, 3H); ESI MS m/z 361[M+H]⁺.

Preparation of1-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)ethanone(Example Compound 36)

Step 1: To a suspension of AlCl₃ (313 mg, 2.35 mmol) in CH₂Cl₂ (20 mL)was added 63 (100 mg, 0.47 mmol) and AcCl (184 mg, 2.35 mmol). Thereaction mixture was stirred at rt for 6 h. The reaction was quenchedwith methanol (10 mL) carefully and the pH adjusted to neutral withsolid Na₂CO₃. The mixture was filtered through a layer of Celite and thefiltrate was concentrated. Purification by chromatography (silica gel,0-10% methanol/dichloromethane) afforded 67 (82 mg, 68%) as an off-whitesolid: ¹H NMR (300 MHz, DMSO-d₆) δ 12.8 (s, 1H), 8.67 (s, 1H), 8.57 (s,1H), 8.21 (s, 1H), 2.71 (s, 3H), 2.45 (s, 3H), 2.26 (s, 3H); ESI MS m/z256 [M+H]⁺.

Step 2: To a solution of 67 (62 mg, 0.24 mmol) in DMF (0.5 mL) and CH₃CN(5 mL) was added potassium carbonate (67 mg, 0.48 mmol) and benzylchloride (37 mg, 0.29 mmol). The reaction was stirred at 70° C. for 16h. The reaction mixture was filtered through a layer of Celite and thefiltrate was concentrated. Purification by chromatography (silica gel,0-50% ethyl acetate/dichloromethane) afforded Example Compound 36 (30mg, 36%) as an off-white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.59 (d, J=1.5Hz, 1H), 8.22 (s, 1H), 7.45 (d, J=1.8 Hz, 1H), 7.40-7.36 (m, 3H),7.21-7.18 (m, 2H), 5.40 (s, 2H), 2.89 (s, 3H), 2.34 (s, 3H), 2.17 (s,3H); ESI MS m/z 346 [M+H]⁺.

Preparation of1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-ylformate (Example Compound 37)

Step 1: A solution of Example Compound 56 (165 mg, 0.52 mmol) in DMF (2mL) was added POCl₃ (159 mg, 1.03 mmol). The reaction mixture was heatedat 100° C. for 2 h and concentrated. The residue was dissolved in CH₂Cl₂(100 mL), washed with saturated NaHCO₃ (2×20 mL) and brine (20 mL). Theorganic layer was dried over sodium sulfate, filtered and concentrated.Purification by chromatography (silica gel, 0-50% ethylacetate/dichloromethane) afforded Example Compound 37 (81 mg, 45%) as ayellow solid: ¹H NMR (300 MHz, CDCl₃) δ 9.90 (s, 1H), 7.62 (s, 1H),7.43-7.41 (m, 3H), 7.28 (s, 1H), 7.22-7.18 (m, 3H), 5.31 (s, 2H), 2.22(s, 3H), 2.10 (s, 3H); ESI MS m/z 348 [M+H]⁺.

Preparation of4-((6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)benzamide(Example Compound 38)

To a solution of Example Compound 70 (100 mg, 0.29 mmol) in ethanol (3mL) was added 2N sodium hydroxide in water (1.46 mL, 2.9 mmol). Themixture was heated to 85° C. for 20 min, then cooled to roomtemperature, and neutralized with 2 mL of acetic acid. The mixture wasbasified (pH 8) with solid sodium carbonate, diluted in methylenechloride (100 mL), washed with brine (20 mL), and dried over anhydroussodium sulfate. After filtration, the filtrate was concentrated in vacuoand purified by chromatography (silica gel, 0-20% methanol/methylenechloride) to afford Example Compound 38 as a white solid (71 mg, 68%):¹H NMR (300 MHz, DMSO-ds) δ 8.35 (d, J=1.8 Hz, 1H), 7.99 (d, J=2.1 Hz,1H), 7.94 (br s, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.37 (br s, 1H), 7.27 (d,J=8.4 Hz, 2H), 5.61 (s, 2H), 2.60 (s, 3H), 2.39 (s, 3H), 2.21 (s, 3H);ESI m/z 362 [M+H]⁺.

Preparation of4-(1-benzyl-3-nitro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole(Example Compound 39)

Step 1: To a solution of 63 (100 mg, 0.47 mmol) in H₂SO₄ (0.5 mL) at 0°C. was added HNO₃ (35 mg, 0.47 mmol). The reaction mixture was stirredat 0° C. for 1 h. The reaction mixture was diluted with H₂O (10 mL) andadjusted to neutral pH with 6N NaOH solution. The solution was extractedwith CH₂Cl₂ (30 mL). The organic layer was dried, filtered andconcentrated. Purification by chromatography (silica gel, 0-10%methanol/dichloromethane) afforded 68 (82 mg, 68%) as a yellow solid: ¹HNMR (300 MHz, DMSO-d₆) δ 12.9 (s, 1H), 8.85 (s, 1H), 8.58 (d, J=2.1 Hz,1H), 7.95 (d, J=1.8 Hz, 1H), 2.45 (s, 3H), 2.26 (s, 3H); ESI MS m/z 259[M+H]⁺.

Step 2: To a solution of 68 (82 mg, 0.32 mmol) in DMF (0.5 mL) and CH₃CN(5 mL) was added potassium carbonate (88 mg, 0.64 mmol) and benzylchloride (44 mg, 0.35 mmol). The reaction was stirred at 70° C. for 16h. The reaction mixture was filtered through a layer of Celite and thefiltrate was concentrated. Purification by chromatography (silica gel,0-50% ethyl acetate/dichloromethane) afforded Example Compound 39 (68mg, 61%) as an off-white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.74 (s, 1H),8.47 (s, 1H), 7.56 (s, 1H), 7.45-7.42 (m, 3H), 7.27-7.26 (m, 2H), 5.47(s, 2H), 2.35 (s, 3H), 2.17 (s, 3H); ESI MS m/z 349 [M+H]⁺.

Preparation of1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-amine(Example Compound 17)

Step 1: A mixture of 37 (200 mg, 0.709 mmol) in tetraethoxymethane (340mg, 1.77 mmol) was heated at 100° C. for 4 h. The reaction mixture wascooled to room temperature, concentrated and purified by chromatography(silica gel, 0-50% ethyl acetate in hexanes) to afford 69 (177 mg, 74%)as a yellow solid: ¹H NMR (500 MHz, CD₃OD) δ 7.30-7.15 (m, 2H), 4.57 (q,J=7.0 Hz, 2H), 2.39 (s, 3H), 2.23 (s, 3H), 1.47 (t, J=7.0 Hz, 3H); ESIm/z 336 [M+H]⁺.

Step 2: To a solution of 69 (250 mg, 0.74 mmol) in CH₃CN (8 mL) and DMF(2 mL) was added K₂CO₃ (155 mg, 0.82 mmol) and benzyl chloride (104 mg,0.82 mmol). The reaction was heated at 60° C. for 16 h. The mixture wasdiluted with ethyl acetate (100 mL), filtered and concentrated. Theresidue was purified by chromatography (silica gel, 0-30% EtOAc/hexanes)to afford 70 (200 mg, 63%) as an off-white solid and 71 (87 mg, 27%) asa colorless oil: 70: ¹H NMR (300 MHz, CDCl₃) δ 7.34-7.29 (m, 3H),7.21-7.18 (m, 3H), 6.77 (d, J=1.5 Hz, 1H), 5.16 (s, 2H), 4.75 (q, J=7.5Hz, 2H), 2.29 (s, 3H), 2.14 (s, 3H), 1.50 (t, J=7.0 Hz, 3H); 71: ¹H NMR(300 MHz, CDCl₃) δ 7.37 (d, J=1.5 Hz, 1H), 7.34-7.28 (m, 3H), 7.18 (d,J=7.5 Hz, 2H), 7.12 (d, J=1.5 Hz, 1H), 5.60 (s, 2H), 4.63 (q, J=7.0 Hz,2H), 2.41 (s, 3H), 2.28 (s, 3H), 1.45 (t, J=7.0 Hz, 3H).

Step 3: A mixture of 70 (100 mg, 0.235 mmol), BocNH₂ (82 mg, 0.705mmol), Xantphos (28 mg, 0.048 mmol), Pd₂(dba)₃ (22 mg, 0.024 mmol) andCs₂CO₃ (268 mg, 0.823 mmol) in 1,4-dioxane (8 mL) was purged withnitrogen and heated at 100° C. for 18 h. The mixture was diluted withmethylene chloride (200 mL) and filtered. The filtrate was concentratedand purified by chromatography (silica gel, 0-30% EtOAc/hexanes) toafford 72 (90 mg, 83%) as an off-white solid: ¹H NMR (300 MHz, CDCl₃) δ7.74 (br s, 1H), 7.41 (s, 1H), 7.32-7.29 (m, 3H), 7.22-7.19 (m, 2H),6.51 (d, J=1.5 Hz, 1H), 5.14 (s, 2H), 4.64 (q, J=7.2 Hz, 2H), 2.32 (s,3H), 2.17 (s, 3H), 1.49 (t, J=7.2 Hz, 3H), 1.46 (s, 9H).

Step 4: A solution of 72 (90 mg, 0.195 mmol) in TFA (1 mL) and CH₂Cl₂ (2mL) was stirred at rt for 1 h. The mixture was concentrated, the residuewas dissolved in ethyl acetate (100 mL) and washed with saturated NaHCO₃(50 mL×2). The organic layer was dried over sodium sulfate, filtered andconcentrated. Purification by chromatography (silica gel, 40-100%EtOAc/hexanes) afforded Example Compound 17 (51 mg, 72%) as an off-whitesolid: ¹H NMR (300 MHz, CDCl₃) δ 7.35-7.20 (m, 5H), 6.33 (d, J=1.5 Hz,1H), 6.30 (d, J=1.5 Hz, 1H), 5.13 (s, 2H), 4.68 (q, J=6.9 Hz, 2H), 4.30(br s, 2H), 2.30 (s, 3H), 2.16 (s, 3H), 1.49 (t, J=7.2 Hz, 3H); ESI m/z363 [M+H]⁺.

Preparation of4-(1-benzyl-2-ethoxy-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole(Example Compound 59)

To a mixture of 28 (50 mg, 0.17 mmol) and tetraethyl orthocarbonate (131mg, 0.68 mmol) was added sulfamic acid (3 mg, 0.034 mmol). The mixturewas then heated to 100° C. for 8 h, then diluted with ethyl acetate (30mL), washed with brine (15 mL), dried over anhydrous sodium sulfate, andconcentrated in vacuo. The residue was purified by chromatography(silica gel, 0-10% methanol/methylene chloride) to afford ExampleCompound 59 (24 mg, 41%) as an off-white solid: ¹H NMR (300 MHz,DMSO-d₆) δ 7.75 (d, J=1.2 Hz, 1H), 7.38-7.22 (m, 5H), 7.18 (d, J=1.5 Hz,1H), 4.99 (s, 2H), 4.34 (q, J=7.2 Hz, 2H), 2.37 (s, 3H), 2.18 (s, 3H),1.42 (t, J=7.2 Hz, 3H); ESI m/z 349 [M+H]⁺.

Preparation of1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carbonitrile(Example Compound 85)

Compound 73 was prepared by following the method for General Procedure Jsteps 1 to 3 starting with 2-amino-5-bromobenzonitrile. Using theprocedure used for General Procedure D step 3 on compound 73 (30 mg,0.09 mmol) afforded Example Compound 85 (10 mg, 31%) as an off-whitesolid: ¹H NMR (500 MHz, CD₃OD) δ 7.63 (d, J=1.5 Hz, 1H), 7.60 (d, J=1.5Hz, 1H), 7.38-7.27 (m, 3H), 7.19-7.14 (m, 2H), 5.57 (s, 2H), 2.69 (s,3H), 2.32 (s, 3H), 2.16 (s, 3H); ESI m/z 343 [M+H]⁺.

General Procedure O Preparation ofN-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetamide(Example Compound 111)

A solution of Example Compound 16 (34 mg, 0.10 mmol), acetic anhydride(12 mg, 0.12 mmol) and i-Pr₂NEt (26 mg, 0.20 mmol) in THF (3 mL) wasstirred at rt for 16 h. The mixture was concentrated, and the residuewas purified by chromatography (silica gel, 0-5% methanol/EtOAc) toafford Example Compound 111 (28 mg, 74%) as a white solid: ¹H NMR (300MHz, DMSO-d₆) δ 10.78 (s, 1H), 9.85 (s, 1H), 7.60-7.46 (m, 5H), 7.28 (d,J=1.2 Hz, 1H), 7.06 (d, J=1.2 Hz, 1H), 5.22 (s, 2H), 2.51 (s, 3H), 2.33(s, 3H), 2.27 (s, 3H); ESI m/z 377 [M+H]⁺.

General Procedure P Preparation of6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one(Example Compound 110) and4-amino-6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one(Example Compound 115)

Step 1: To a solution of 30 (1.00 g, 3.21 mmol) in toluene (70 mL) undernitrogen atmosphere was added benzyl amine (1.94 g, 16.0 mmol),potassium tert-butoxide (539 mg, 4.82 mmol),2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (229 mg,0.482 mmol), and tris(dibenzylideneacetone) dipalladium(O) (293 mg,0.321 mmol). The reaction mixture was heated at 90° C. overnight, cooledto room temperature, and purified by chromatography (silica gel, 0-50%ethyl acetate in hexanes) to afford 74 (700 mg, 62%) as a red-brownsolid: ¹H NMR (500 MHz, CDCl₃) δ 7.50 (d, J=1.8 Hz, 1H), 7.70-7.22 (m,5H), 6.41 (d, J=1.6 Hz, 1H), 6.07 (s, 2H), 4.48 (q, J=3.5 Hz, 1H), 3.65(s, 1H), 2.05 (s, 3H), 1.90 (s, 3H), 1.62 (d, J=6.6 Hz, 3H); ESI m/z 353[M+H]⁺.

Step 2: To a mixture of 74 (600 mg, 1.70 mmol) in 1,4-dioxane (40 mL)was added 1,1′-carbonyldiimidazole (2.76 mg, 17.0 mmol) and DMAP (acrystal). The reaction was heated in a sealed tube at 120° C. for 2days. The mixture was concentrated and purified by chromatography(silica gel, 0-100% ethyl acetate in hexanes) to give Example Compound110 (420 mg, 65%) as an orange solid: ¹H NMR (500 MHz, CD₃OD) δ 7.75 (d,J=1.3 Hz, 1H), 7.44 (d, J=7.7 Hz, 2H), 7.38 (t, J=7.7 Hz, 2H), 7.31 (t,J=7.7 Hz, 1H), 6.88 (d, J=1.3 Hz, 1H), 5.88 (q, J=7.1 Hz, 1H), 2.20 (s,3H), 2.02 (s, 3H), 1.91 (d, J=7.2 Hz, 3H); ESI m/z 377 [M−H]⁺.

Step 3: To a solution of Example Compound 110 (100 mg, 0.265 mmol) intetrahydrofuran (10 mL) was added sodium dithionite (276 mg, 1.59 mmol)in water (10 mL). The reaction mixture was stirred at room temperatureovernight and concentrated under vacuum. The residue was added 2N HCland heated to just boiling, cooled to room temperature, and concentratedin vacuum. The residue was dissolved in MeOH and basified by cone.NH₄OH, concentrated, and purified by chromatography (silica gel, 0-100%hexanes/ethyl acetate). It was further purified by reverse phase HPLC ona Polaris Cig column eluted with 10-90% CH₃CN in H₂O to give ExampleCompound 115 (49 mg, 53%) as an off-white solid: ¹H NMR (500 MHz, CD₃OD)δ 7.42-7.32 (m, 4H), 7.26 (t, J=6.9 Hz, 1H), 6.35 (s, 1H), 5.94 (s, 1H),5.78 (q, J=7.2 Hz, 1H), 2.17 (s, 3H), 2.00 (s, 3H), 1.86 (d, J=7.2 Hz,3H); ESI m/z 349 [M+H]⁺.

General Procedure Q Preparation of4-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)morpholine(Example Compound 114)

A mixture of Example Compound 10 (90 mg, 0.28 mmol) and phosphorus (V)oxychloride (1 mL) was heated to 110° C. for 5 h, then cooled to roomtemperature. The mixture was concentrated, dissolved with methylenechloride (75 mL), and washed with saturated sodium bicarbonate solution(20 mL). The organic layer was dried over sodium sulfate, filtered, andconcentrated. The residue was dissolved in a 2.0 M solution ofmorpholine in tetrahydrofuran (5.6 mL, 11.2 mmol) and the mixture washeated to 75° C. for 3 h. The reaction mixture was concentrated, and theresidue was purified by chromatography (silica gel, 0-5%methanol/methylene chloride), and then triturated with ethylacetate/hexanes to afford Example Compound 114 (62 mg, 57%) as a whitesolid: ¹H NMR (500 MHz, CDCl₃) δ 8.24 (d, J=2.0 Hz, 1H), 7.41-7.34 (m,3H), 7.15 (d, J=6.5 Hz, 2H), 7.06 (d, J=1.0 Hz, 1H), 5.26 (s, 2H), 3.83(t, J=4.5 Hz, 4H), 3.50 (t, J=4.5 Hz, 4H), 2.29 (s, 3H), 2.11 (s, 3H);ESI m/z 390 [M+H]⁺.

General Procedure R Preparation of1-(3,4-dichlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one(Example Compound 101)

Compound 75 was prepared according to General Procedure D, steps 1-2.

To a solution of 75 (218 mg, 0.60 mmol) in 1,4-dioxane (5 mL) was added1,1′-carbonyldiimidazole (117 mg, 0.72 mmol), and the mixture was heatedto 100° C. for 16 h. The mixture was diluted with methylene chloride (70mL), and washed with brine (20 mL). The organic layer was dried oversodium sulfate, filtered, and concentrated. The residue was purified bychromatography (silica gel, 0-10% methanol/methylene chloride) to affordExample Compound 101 (155 mg, 66%) as a white solid: ¹H NMR (500 MHz,DMSO-d₆) δ 11.83 (s, 1H), 7.92 (d, J=1.5 Hz, 1H), 7.73 (d, J=2.0 Hz,1H), 7.61 (d, J=8.0 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.35 (dd, J=8.5,2.0 Hz, 1H), 5.05 (s, 2H), 2.37 (s, 3H), 2.19 (s, 3H); ESI m/z 389[M+H]⁺.

General Procedure S Preparation of(S)-3,5-dimethyl-4-(2-methyl-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-6-yl)isoxazole(Example Compound 125) and(S)-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1-(1-phenylethyl)-1H-benzo[d]imidazol-4-amine(Example Compound 143)

Compound 76 was prepared by following the method of General Procedure Pstep 1 starting with (S)-1-phenylethanamine.

Step 1: Using the procedure used in General Procedure F step 1 startingwith compound 76 (140 mg, 0.40 mmol) afforded Example Compound 125 (108mg, 72%) as a yellow solid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.87 (d, J=1.5Hz, 1H), 7.42-7.30 (m, 6H), 6.11 (q, J=7.2 Hz, 1H), 2.74 (s, 3H), 2.23(s, 3H), 2.04 (s, 3H), 1.94 (d, J=6.9 Hz, 3H); ESI MS m/z 377 [M+H]⁺.

Step 2: Using the procedure used in General Procedure P step 3 startingwith compound Example Compound 125 (80 mg, 0.21 mmol) afforded ExampleCompound 143 (53 mg, 72%) as an off-white solid: ¹H NMR (300 MHz,DMSO-d₆) δ 7.39-7.26 (m, 5H), 6.23 (d, J=1.5 Hz, 1H), 6.14 (d, J=1.2 Hz,1H), 5.86 (q, J=7.2 Hz, 1H), 5.26 (s, 2H), 2.58 (s, 3H), 2.20 (s, 3H),2.02 (s, 3H), 1.86 (d, J=6.9 Hz, 3H); ESI MS m/z 347 [M+H]⁺.

General Procedure T Preparation of4-(1-benzyl-2-(pyridin-3-yloxy)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole(Example Compound 236)

A mixture of Example Compound 10 (100 mg, 0.31 mmol) and phosphorus (V)oxychloride (1 mL) was heated to 110° C. for 5 h, then cooled to roomtemperature. The mixture was concentrated, dissolved with methylenechloride (75 mL), and washed with saturated sodium bicarbonate solution(20 mL). The organic layer was dried over sodium sulfate, filtered, andconcentrated. The residue was dissolved in N,N-dimethylformamide (2.5mL), 3-hydroxypyridine (109 mg, 1.15 mmol) and potassium carbonate (175mg, 1.27 mmol) were added. The mixture was heated to 100° C. for 16 h,then diluted with ethyl acetate (75 mL), washed with brine (2×25 mL),dried over sodium sulfate, filtered and concentrated. The residue waspurified by chromatography (silica gel, 0-10% methanol/methylenechloride) to afford Example Compound 236 (58 mg, 47%) as a light brownsolid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.74 (d, J=2.7 Hz, 1H), 8.57 (dd,J=4.5, 0.9 Hz, 1H), 8.27 (d, J=1.8 Hz, 1H), 8.02-7.98 (m, 2H), 7.59 (dd,J=8.4, 4.5 Hz, 1H), 7.47 (d, J=6.9 Hz, 2H), 7.42-7.30 (m, 3H), 5.53 (s,2H), 2.40 (s, 3H), 2.22 (s, 3H); ESI m/z 398 [M+H]⁺.

Preparation of6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-2-amine(Example Compound 127) and6-(3,5-dimethylisoxazol-4-yl)-N²-ethyl-1-(1-phenylethyl)-1H-benzo[d]imidazole-2,4-diamine(Example Compound 134)

Step 1: To Example Compound 110 (200 mg, 0.529 mmol) was addedphosphorus(V) oxychloride (2 mL, 21.5 mmol) and N,N-dimethylformamide(one drop). The reaction was heated at 90° C. overnight. The mixture wasconcentrated, the residue was dissolved in tetrahydrofuran (5 mL),ethylamine (10 mL, 1M in tetrahydrofuran) was added. The reactionmixture was heated in a sealed tube at 70° C. for 2 days. The mixturewas concentrated and purified by chromatography (silica gel, 0-100%ethyl acetate in hexanes) to give Example Compound 127 (40 mg, 19%) as ayellow solid: ¹H NMR (500 MHz, CD₃OD) δ 7.70 (d, J=1.5 Hz, 1H),7.45-7.30 (m, 5H), 6.72 (d, J=1.5 Hz, 1H), 5.86 (q, J=7.0 Hz, 1H), 3.72(q, J=7.2 Hz, 2H), 2.17 (s, 3H), 1.98 (s, 3H), 1.90 (d, J=7.0 Hz, 3H),1.36 (t, J=7.2 Hz, 3H); ESI m/z 406 [M−H]⁺.

Step 2: To a solution of Example Compound 127 (35 mg, 0.086 mmol) intetrahydrofuran (10 mL) was added sodium dithionite (90 mg, 0.52 mmol)in water (10 mL). The reaction mixture was stirred at room temperatureovernight and concentrated under vacuum. The residue was added 2N HCland heated to just boiling, cooled to room temperature, and concentratedin vacuum. The residue was dissolved in MeOH and basified by cone.NH₄OH, concentrated, and purified by chromatography (silica gel, 0-100%hexanes/ethyl acetate). It was further purified by reverse phase HPLC ona Polaris Cig column eluting with 10-90% CH₃CN in H₂O to give ExampleCompound 134 (15 mg, 47%) as an off-white solid: ¹H NMR (500 MHz, CD₃OD)δ 7.40-7.25 (m, 5H), 6.31 (d, J=1.5 Hz, 1H), 5.92 (d, J=1.5 Hz, 1H),5.72 (q, J=6.9 Hz, 1H), 3.53 (q, J=7.2 Hz, 2H), 2.15 (s, 3H), 1.99 (s,3H), 1.86 (d, J=7.0 Hz, 3H), 1.33 (t, J=7.2 Hz, 3H); ESI m/z 376 [M+H]⁺.

Preparation of1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-3-methyl-4-nitro-1H-benzo[d]imidazol-2(3H)-one(Example Compound 150) and4-amino-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one(Example Compound 162)

Step 1: A mixture of Example Compound 15 (73 mg, 0.20 mmol), CH₃I (85mg, 0.60 mmol) and K₂CO₃ (110 mg, 0.8 mmol) in DMF (3 mL) was stirred atrt for 16 h. The reaction mixture was diluted with EtOAc (100 mL) andwashed with brine (3×50 mL). The organic layer was dried over sodiumsulfate, filtered and concentrated. The residue was triturated withEtOAc/hexanes to afford Example Compound 150 (65 mg, 86%) as a yellowsolid: ¹H NMR (300 MHz, CDCl₃) δ 7.48 (d, J=1.5 Hz, 1H), 7.35-7.30 (m,5H), 6.84 (d, J=1.5 Hz, 1H), 5.15 (s, 2H), 3.65 (s, 3H), 2.26 (s, 3H),2.09 (s, 3H); ESI m/z 379 [M+H]⁺.

Step 2: To a solution of Example Compound 150 (57 mg, 0.15 mmol) in THF(5 mL) and water (4 mL) was added Na₂S₂O₄ (153 mg, 0.90 mmol). Themixture was stirred at rt for 4 h, 2N HCl (1 mL) was added, the mixturewas heated to reflux for 15 minutes. After cooled to rt, Na₂CO₃ wasadded slowly to adjust to pH 9. The mixture was extracted with CH₂Cl₂(100 mL), the organic layer was washed with brine (50 mL), filtered,concentrated and purified by chromatography (silica gel, 0-10%methanol/ethyl acetate) to afford Example Compound 162 (60 mg, 72%) as awhite solid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.36-7.24 (m, 5H), 6.40 (d,J=1.5 Hz, 1H), 6.39 (d, J=1.8 Hz, 1H), 5.08 (s, 2H), 4.99 (s, 2H), 3.62(s, 3H), 2.29 (s, 3H), 2.12 (s, 3H); ESI m/z 349 [M+H]⁺. HPLC>99%

Preparation of4-(1-benzyl-2-methyl-4-(methylsulfonyl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole(Example Compound 168)

A mixture of Example Compound 121 (100 mg, 0.25 mmol), sodiummethanesulfinate (39 mg, 0.38 mmol), CuI (5 mg, 0.025 mmol), L-proline(6 mg, 0.05 mmol) and NaOH (2 mg, 0.05 mmol) in DMSO (3 mL) was heatedat 150° C. in a microwave reactor for 2 h. The mixture was diluted withethyl acetate (100 mL) and washed with brine (50 mL). The organic layerwas dried over Na₂SO₄, filtered and concentrated. The residue waspurified by chromatography (silica gel, 50-100% EtOAc/hexanes) to affordExample Compound 168 (13 mg, 13%) as an off-white solid: ¹H NMR (300MHz, CDCl₃) δ 7.75 (d, J=1.5 Hz, 1H), 7.37-7.33 (m, 3H), 7.24 (d, J=1.5Hz, 1H), 7.11-7.08 (m, 2H), 5.39 (s, 2H), 3.54 (s, 3H), 2.73 (s, 3H),2.31 (s, 3H), 2.16 (s, 3H); ESI m/z 396 [M+H]⁺. HPLC 92.3%.

Preparation of4-(1-benzyl-2,7-dimethyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole(Example Compound 181)

Step 1: To a solution of 77 (4.4 g, 16.5 mmol) in 1,4-dioxane (100 mL)was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(4.4 g, 19.8 mmol), Na₂CO₃ (2.0 M in H₂O, 25 mL, 50.0 mmol) andtetrakis(triphenylphosphine)palladium(0) (959 mg, 0.83 mmol). Thereaction mixture was purged with nitrogen and heated at 80° C. for 16 h.The mixture was diluted with EtOAc (100 mL) and washed with brine (50mL). The organic layer was dried over Na₂SO₄, and filtered. The filtratewas concentrated and then purified by chromatography (silica gel, 0-60%ethyl acetate/hexanes) to afford 78 (2.64 g, 57%) as an off-white solid:¹H NMR (300 MHz, DMSO-d₆) δ 7.71 (s, 1H), 6.32 (s, 2H), 2.22 (s, 3H),2.08 (s, 3H), 2.02 (s, 3H).

Step 2: A mixture of 78 (1.3 g, 4.61 mmol), benzylamine (2.51 mL, 23.05mmol), X-phos (658 mg, 1.38 mmol), Pd₂(dba)₃ (632 mg, 0.69 mmol) andf-BuOK (774 mg, 6.92 mmol) in toluene (50 mL) was purged with nitrogenfor 10 minutes and then heated at 90° C. for 18 h. The mixture wasdiluted with methylene chloride (200 mL) and filtered. The filtrate wasconcentrated and purified by chromatography (silica gel, 0-100%EtOAc/hexanes) to afford 79 (125 mg, 9%) as a brown gum: ¹H NMR (300MHz, DMSO-d₆) δ 7.38 (s, 1H), 7.31-7.22 (m, 5H), 5.68 (s, 2H), 4.28 (t,J=7.5 Hz, 1H), 4.01 (d, J=7.0 Hz, 2H), 2.14 (s, 3H), 1.93 (s, 3H), 1.74(s, 3H).

Step 3: To a solution of 79 (80 mg, 0.26 mmol) in triethylorthoacetate(2 mL) was added AcOH (0.2 mL). The mixture was heated to 120° C. for 2h. The mixture was concentrated, the residue was dissolved in EtOAc (100mL) and washed with saturated NaHCO₃ (50 mL×2). The organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was purifiedby chromatography (silica gel, 0-10% MeOH/ethyl acetate) to affordExample Compound 181 (39 mg, 45%) as an off-white solid: ¹H NMR (300MHz, CDCl₃) δ 8.23 (s, 1H), 7.37-7.31 (m, 3H), 6.95-6.92 (m, 2H), 5.58(s, 2H), 2.64 (s, 3H), 2.23 (s, 3H), 2.22 (s, 3H), 2.06 (s, 3H); ESI m/z333 [M+H]⁺.

Preparation of1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-7-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one(Example Compound 180)

A mixture of 79 (31 mg, 0.10 mmol) and CDI (33 mg, 0.2 mmol) in dioxane(3 mL) was heated to 120° C. for 16 h. The mixture was concentrated, theresidue was purified by chromatography (silica gel, 50-100% ethylacetate/hexanes) to afford Example Compound 180 (10 mg, 30%) as anoff-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.89 (s, 1H), 7.74 (s,1H), 7.38-7.24 (m, 3H), 7.17-7.14 (m, 2H), 5.26 (s, 2H), 2.16 (s, 3H),2.01 (s, 3H), 1.99 (s, 3H); ESI m/z 335 [M+H]⁺.

Preparation of3,5-dimethyl-4-(2-methyl-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole(Example Compound 108)

Step 1: To a suspension of 27 (660 mg, 3.23 mmol) in acetonitrile (33mL) was added (1-bromoethyl)benzene (658 mg, 3.55 mmol) and potassiumcarbonate (893 mg, 6.46 mmol). The mixture was heated to 60° C. for 16hours, then cooled, diluted with methylene chloride (120 mL) and washedwith brine (40 mL). The organic layer was dried over sodium sulfate,filtered and concentrated. The residue was purified by chromatography(silica gel, 0-10% methanol/methylene chloride) to afford 57 (256 mg,26%) as white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 7.36 (d, J=1.5 Hz, 2H),7.30 (t, J=7.5 Hz, 2H), 7.20-7.17 (m, 2H), 6.15 (d, J=2.0 Hz, 1H), 5.82(s, 2H), 5.40 (d, J=5.5 Hz, 1H), 4.51-4.45 (m, 1H), 2.05 (s, 3H), 1.84(s, 3H), 1.48 (d, J=7.0 Hz, 3H).

Step 2: To a solution of 57 (41 mg, 0.13 mmol) in triethylorthoacetate(0.24 mL, 1.33 mmol) was added acetic acid (20 μL, 0.36 mmol). Themixture was heated to 100° C. for 1 h, then one drop of concentrated HClwas added. The mixture was heated to 100° C. for 10 min. The mixture wasbasified with saturated sodium bicarbonate, diluted with methylenechloride (45 mL) and washed with brine (20 mL). The organic layer wasdried over sodium sulfate, filtered and concentrated. The residue waspurified by chromatography (silica gel, 0-3% methanol/methylenechloride) followed by trituration with methylene chloride/hexanes toafford Example Compound 108 (11 mg, 28%) as white solid: ¹H NMR (500MHz, DMSO-d₆) δ 8.27 (d, J=2.0 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H),7.40-7.36 (m, 4H), 7.33-7.30 (m, 1H), 6.01 (q, J=7.0 Hz, 1H), 2.70 (s,3H), 2.26 (s, 3H), 2.06 (s, 3H), 1.93 (d, J=7.0 Hz, 3H); ESI m/z 333[M+H]⁺.

Preparation of6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one(Example Compound 112) and6-(3,5-dimethylisoxazol-4-yl)-W-ethyl-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-2-amine(Example Compound 113)

Step 1: To a suspension of 57 (250 mg, 0.81 mmol) in 1,4-dioxane (6 mL),was added 1,1′-carbonyldiimidazole (158 mg, 0.97 mmol). The mixture waspurged with nitrogen for 5 min, and then heated to 100° C. for 16 h. Themixture was diluted with methylene chloride (100 mL), filtered andconcentrated. The residue was purified by chromatography (silica gel,0-5% methanol/methylene chloride) then triturated with methylenechloride/hexanes to afford Example Compound 112 (258 mg, 95%) asoff-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.78 (s, 1H), 7.87 (d,J=2.0 Hz, 1H), 7.44 (d, J=7.5 Hz, 2H), 7.36 (t, J=7.5 Hz, 2H), 7.29 (t,J=7.5 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H), 5.72 (q, J=7.0 Hz, 1H), 2.26 (s,3H), 2.06 (s, 3H), 1.84 (d, J=7.0 Hz, 3H); ESI m/z 335 [M+H]⁺.

Step 2: A mixture of Example Compound 112 (100 mg, 0.30 mmol) andphosphorus (V) oxychloride (1 mL) was heated to 110° C. for 5 h, andcooled to room temperature. The reaction mixture was concentrated,diluted with methylene chloride (75 mL), and washed with saturatedsodium bicarbonate solution (20 mL). The organic layer was dried oversodium sulfate, filtered, and concentrated. The residue was dissolved ina 2.0 M solution of ethylamine in tetrahydrofuran (6.0 mL, 12.0 mmol)and the mixture was heated to 75° C. for 7 h. The reaction mixture wasconcentrated, and the residue was purified by chromatography (silicagel, 0-5% methanol/methylene chloride), then triturated with ethylacetate/hexanes to afford Example Compound 113 (52 mg, 49%) as a whitesolid: ¹H NMR (500 MHz, DMSO-d₆) δ 7.90 (d, J=2.0 Hz, 1H), 7.40-7.28 (m,6H), 6.81 (d, J=2.0 Hz, 1H), 5.84 (q, J=7.0 Hz, 1H), 3.54-3.48 (m, 2H),2.20 (s, 3H), 1.99 (s, 3H), 1.83 (d, J=7.0 Hz, 3H), 1.27 (t, J=7.0 Hz,3H); ESI m/z 362 [M+H]⁺.

Preparation of6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one(Enantiomer A) (Example Compound 218) and6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one(Enantiomer B) (Example Compound 219)

Example Compound 112 (87 mg) was separated by SFC chiral HPLC (ChiralpakAS-H, 30 mm×250 mm, mobile phase 30% EtOH in CO₂ (0.2% Et₂NH), 120 bar,flow rate 80 mL/min) to afford Example Compound 218 (Enantiomer A) (41mg, 46%) and Example Compound 219 (Enantiomer B) (41 mg, 46%) asoff-white solids.

Example Compound 218 (Enantiomer A): ¹H NMR (500 MHz, DMSO-d₆) δ 11.77(s, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.44 (d, J=7.5 Hz, 2H), 7.37 (t, J=7.5Hz, 2H), 7.29 (t, J=7.5 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H), 5.72 (q, J=7.5Hz, 1H), 2.26 (s, 3H), 2.06 (s, 3H), 1.84 (d, J=7.5 Hz, 3H); ESI m/z 335[M+H]⁺; HPLC (Chiralcel OD, 4.6 mm×250 mm, 10% EtOH in heptane, 1mL/min) >99%, t_(R)=9.4 min.

Example Compound 219 (Enantiomer B): ¹H NMR (500 MHz, DMSO-d₆) δ 11.78(s, 1H), 7.87 (d, J=1.5 Hz, 1H), 7.44 (d, J=7.5 Hz, 2H), 7.36 (t, J=7.5Hz, 2H), 7.29 (t, J=7.5 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 5.72 (q, J=7.5Hz, 1H), 2.26 (s, 3H), 2.06 (s, 3H), 1.84 (d, J=7.5 Hz, 3H); ESI m/z 335[M+H]⁺; HPLC (Chiralcel OD, 4.6 mm×250 mm, 10% EtOH in heptane, 1mL/min) >99%, t_(R)=10.9 min.

Preparation of3-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1-ethyl-1H-benzo[d]imidazol-2(3H)-one(Example Compound 122)

Step 1: To a solution of 20 (214 mg, 0.77 mmol) in 1,4-dioxane (5 mL)was added 1,1′-carbonyldiimidazole (150 mg, 0.93 mmol) and the mixturewas heated to 100° C. for 15 h. The mixture was concentrated andpurified by chromatography (silica gel, 0-20% ethyl acetate/hexanes) toafford 80 (142 mg, 61%) as a white solid; ¹H NMR (500 MHz, DMSO-d₆) δ11.13 (s, 1H), 7.35-7.25 (m, 6H), 7.12 (dd, J=8.5, 2.0 Hz, 1H), 6.94 (d,J=8.0 Hz, 1H), 5.01 (s, 2H).

Step 2: To a solution of 80 (100 mg, 0.33 mmol) in 1,4-dioxane (5 mL)was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(110 mg, 0.49 mmol), potassium carbonate (91 mg, 0.66 mmol), and water(1 mL). The mixture was purged with nitrogen for 10 min,tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmol) was added,and the mixture was heated to 90° C. for 16 h. The mixture was dilutedwith methylene chloride (100 mL), and washed with brine (30 mL). Theorganic layer was dried over sodium sulfate, filtered, and concentrated.The residue was purified by chromatography (silica gel, 0-5%methanol/methylene chloride) then triturated with ethyl acetate/hexanesto afford 81 (55 mg, 52%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ11.07 (s, 1H), 7.40-7.23 (m, 5H), 7.06 (d, J=8.1 Hz, 1H), 7.02 (s, 1H),6.95 (dd, J=7.8, 1.5 Hz, 1H), 5.03 (s, 2H), 2.30 (s, 3H), 2.13 (s, 3H);ESI m/z 320 [M+H]⁺.

Step 3: To a solution of 81 (36 mg, 0.11 mmol) in acetonitrile (3 mL)was added potassium carbonate (109 mg, 0.79 mmol) and iodoethane (80 mg,0.56 mmol), then the mixture was heated to 40° C. for 48 h. The mixturewas diluted with methylene chloride (75 mL), and washed with brine (20mL). The organic layer was dried over sodium sulfate, filtered, andconcentrated. The residue was purified by chromatography (silica gel,0-20% ethyl acetate/methylene chloride), then triturated with ethylacetate/hexanes to afford Example Compound 122 (14 mg, 37%) as ayellow-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 7.37 (d, J=7.5 Hz, 2H),7.33 (t, J=7.0 Hz, 2H), 7.29 (d, J=8.0 Hz, 1H), 7.26 (t, J=7.0 Hz, 1H),7.09 (d, J=1.5 Hz, 1H), 7.03 (dd, J=8.0, 1.5 Hz, 1H), 5.08 (s, 2H), 3.94(q, J=7.0 Hz, 2H), 2.31 (s, 3H), 2.13 (s, 3H), 1.26 (t, J=7.0 Hz, 3H);ESI m/z 348 [M+H]⁺.

Preparation of1-benzyl-N⁶-(3,5-dimethylisoxazol-4-yl)-methyl-1H-benzo[d]imidazole-4,6-diamine(Example Compound 142)

Step 1: To a suspension of 33 (790 mg, 3.09 mmol) in acetonitrile (15mL) was added benzyl chloride (703 mg, 5.55 mmol) and potassiumcarbonate (1.07 g, 7.71 mmol). The reaction mixture was heated to 60° C.for 16 h, then concentrated, and the residue was purified bychromatography (silica gel, 0-30% ethyl acetate/hexanes) to afford 82(813 mg, 76%) as a yellow solid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.33 (d,J=1.8 Hz, 1H), 8.12 (d, J=1.8 Hz, 1H), 7.39-7.27 (m, 3H), 7.13 (d, J=6.6Hz, 2H), 5.62 (s, 2H), 2.60 (s, 3H).

Step 2: To a solution of 82 (150 mg, 0.43 mmol) in toluene (5 mL) wasadded 83 (73 mg, 0.65 mmol), cesium carbonate (282 mg, 0.87 mmol) andXPhos (41 mg, 0.087 mmol). The solution was purged with nitrogen for 5min, then tris(dibenzylideneacetone)dipalladium(0) (40 mg, 0.043 mmol)was added and heated to 110° C. for 16 h. The mixture was filteredthrough celite and concentrated, the residue was purified bychromatography (silica gel, 0-7% methanol/methylene chloride) to afford84 (80 mg, 49%) as a brown oil: ¹H NMR (500 MHz, DMSO-d₆) δ 7.59 (s,1H), 7.34-7.28 (m, 4H), 7.06 (d, J=7.0 Hz, 2H), 6.76 (d, J=2.5 Hz, 1H),5.44 (s, 2H), 2.54 (s, 3H), 2.13 (s, 3H), 1.91 (s, 3H).

Step 3: To a solution of 84 (78 mg, 0.21 mmol) in tetrahydrofuran (5 mL)was added a solution of sodium dithionite (215 mg, 1.24 mmol) in water(4 mL). The mixture was stirred at room temperature for 2 h, the 2N HCl(1 mL) was added, the mixture was heated to reflux for 15 min. Themixture was basified by sodium carbonate, and extracted with methylenechloride (50 mL). The organic layer was dried over sodium sulfate,filtered, and concentrated. The residue was purified by chromatography(silica gel, 0-10% methanol/methylene chloride) to afford ExampleCompound 142 (38 mg, 53%) as a red-brown solid: ¹H NMR (500 MHz,DMSO-d₆) δ 7.31 (t, J=7.5 Hz, 2H), 7.25 (t, J=7.5 Hz, 1H), 7.04 (d,J=7.5 Hz, 2H), 6.69 (s, 1H), 5.73 (d, J=2.0 Hz, 1H), 5.60 (d, J=2.0 Hz,1H), 5.18 (s, 2H), 5.05 (s, 2H), 2.38 (s, 3H), 2.13 (s, 3H), 1.92 (s,3H); ESI m/z 348 [M+H]⁺.

General Procedure U Preparation of1-benzyl-2-methyl-6-(5-methylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine(Example Compound 201)

To a solution of 82 (100 mg, 0.29 mmol) in 1,4-dioxane (5 mL) was added5-methylisoxazole-4-boronic acid pinacol ester (91 mg, 0.43 mmol),sodium carbonate (80 mg, 0.58 mmol), water (1 mL), andtetrakis(triphenylphosphine)palladium(0) (17 mg, 0.01 mmol). Thereaction mixture was purged with nitrogen and heated at 90° C. for 5 h.The mixture was diluted with methylene chloride (70 mL), washed withbrine (25 mL), dried over sodium sulfate, filtered and concentrated. Theresidue was purified by chromatography (silica gel, 0-5% ethylacetate/methylene chloride) to a yellow solid which was dissolved in THF(4 mL), a solution of sodium dithionite (159 mg, 0.91 mmol) in water (2mL) was added and the mixture was stirred at room temperature for 2 h. 2N HCl (1 mL) was added to the mixture, and the mixture was heated toreflux for 15 min. The mixture was basified by saturated aqueous sodiumbicarbonate solution, and extracted with methylene chloride (40 mL×2).The organic layer was dried over sodium sulfate, filtered, andconcentrated. The residue was purified by chromatography (silica gel,0-8% methanol/methylene chloride) and triturated with ethylacetate/hexanes to afford Example Compound 201 (12 mg, 25%) as anoff-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.69 (d, J=0.6 Hz, 1H),7.36-7.26 (m, 3H), 7.15 (d, J=6.9 Hz, 2H), 6.78 (d, J=1.5 Hz, 1H), 6.47(d, J=1.5 Hz, 1H), 5.40 (s, 2H), 5.33 (s, 2H), 2.50 (s, 3H), 2.47 (s,3H); ESI m/z 319 [M+H]⁺.

Preparation ofN-(1-benzyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazol-4-amine(Example Compound 155)

Step 1: To a suspension of 2,3-diamino-5-bromopyridine 26 (1.5 g, 7.98mmol) in methylene chloride (80 mL) was added benzaldehyde (931 mg, 8.78mmol) and acetic acid (40 drops). The mixture was stirred at roomtemperature for 16 h, then washed with saturated sodium bicarbonatesolution (40 mL). The organic layer was dried over sodium sulfate,filtered, and concentrated. The residue was dissolved in methanol (50mL) and sodium borohydride (815 mg, 21.5 mmol) was slowly added. Themixture was stirred at room temperature for 1 h. The mixture was dilutedwith methylene chloride (100 mL), washed with saturated sodiumbicarbonate (40 mL), dried over sodium sulfate, filtered, andconcentrated. The residue was purified by chromatography (silica gel,0-10% methanol/methylene chloride) to afford 85 (1.12 g, 51%) as anoff-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 7.35-7.34 (m, 4H),7.28-7.23 (m, 2H), 6.54 (d, J=2.0 Hz, 1H), 5.78 (s, 2H), 5.73 (t, J=5.5Hz, 1H), 4.30 (d, J=5.5 Hz, 2H).

Step 2: To a suspension of 85 (970 mg, 3.49 mmol) intriethylorthoacetate (5.66 g, 37.9 mmol) was added acetic acid (539 μL,9.42 mmol). The mixture was heated to 100° C. for 40 min. The reactionmixture was basified with saturated sodium bicarbonate (8 mL), dilutedwith methylene chloride (50 mL), and washed with saturated sodiumbicarbonate (30 mL). The organic layer was dried over sodium sulfate,filtered, and concentrated. The residue was purified by chromatography(silica gel, 0-8% methanol/methylene chloride) to afford 86 (305 mg,30%) as a light brown solid: ¹H NMR (500 MHz, DMSO-d₆) δ 8.41 (d, J=2.0Hz, 1H), 8.29 (d, J=2.0 Hz, 1H), 7.35 (t, J=7.0 Hz, 2H), 7.30 (t, J=7.0Hz, 1H), 7.15 (d, J=7.0 Hz, 2H), 5.52 (s, 2H), 2.55 (s, 3H).

Step 3: To a solution of 86 (80 mg, 0.26 mmol) in toluene (5 mL), wasadded 83 (44 mg, 0.40 mmol), cesium carbonate (173 mg, 0.53 mmol), andXPhos (25 mg, 0.053 mmol). The solution was purged with nitrogen for 5min, then tris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.026 mmol)was added. The mixture was heated to 110° C. for 16 h. The reactionmixture was diluted with methylene chloride (20 mL), filtered throughcelite, and concentrated. The residue was purified by chromatography(silica gel, 0-10% methanol/methylene chloride) then triturated withmethylene chloride/hexanes to afford Example Compound 155 (40 mg, 45%)as a light-brown solid: ¹H NMR (500 MHz, DMSO-d₆) δ 7.88 (d, J=2.5 Hz,1H), 7.34-7.30 (m, 3H), 7.27 (t, J=7.0 Hz, 1H), 7.05 (d, J=7.0 Hz, 2H),6.71 (d, J=2.5 Hz, 1H), 5.38 (s, 2H), 2.47 (s, 3H), 2.14 (s, 3H), 1.92(s, 3H); ESI m/z 334 [M+H]⁺.

Preparation of1-benzyl-2-methyl-6-(1-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazo[4,5-b]pyridine(Example Compound 206)

To a solution of 86 (100 mg, 0.33 mmol) in 1,4-dioxane (5 mL) was added1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-1,2,3-triazole(138 mg, 0.66 mmol), K₂CO₃ (137 mg, 0.99 mmol), water (1 mL), andtetrakis(triphenylphosphine)palladium(0) (19 mg, 0.02 mmol). Thereaction mixture was purged with nitrogen and heated at 90° C. for 16 h.The mixture was diluted with ethyl acetate (70 mL), washed with brine(25 mL), dried over sodium sulfate, filtered and concentrated. Theresidue was purified by chromatography (silica gel, 0-8%methanol/methylene chloride) followed by trituration with methylenechloride/hexanes to afford Example Compound 206 (14 mg, 14%) as a whitesolid; ¹H NMR (500 MHz, DMSO-d₆) δ 8.54 (d, J=2.5 Hz, 1H), 8.27 (d,J=2.0 Hz, 1H), 7.96 (s, 1H), 7.35 (t, J=7.0 Hz, 2H), 7.29 (t, J=7.0 Hz,1H), 7.21 (d, J=7.0 Hz, 2H), 5.58 (s, 2H), 4.07 (s, 3H), 2.60 (s, 3H);ESI m/z 305 [M+H]⁺.

Preparation of1-benzyl-2-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyridine(Example Compound 154)

1-Benzyl-2-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyridine(Example Compound 154) was prepared by following the similar method forthe preparation of Example Compound 206 as an off-white solid: ¹H NMR(500 MHz, DMSO-d₆) δ 8.48 (d, J=2.0 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H),7.50 (d, J=2.0 Hz, 1H), 7.35 (t, J=7.0 Hz, 2H), 7.29 (t, J=7.0 Hz, 1H),7.21 (d, J=7.0 Hz, 2H), 6.46 (d, J=2.0 Hz, 1H), 5.57 (s, 2H), 3.83 (s,3H), 2.60 (s, 3H); ESI m/z 304 [M+H]⁺.

Preparation of4-(1-benzyl-2-cyclopropyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole(Example Compound 138)

To a solution of diamine 28 (100 mg, 0.340 mmol) in 1,4-dioxane (2 mL)was added cyclopropanecarboxaldehyde (29 mg, 0.408 mmol) and acetic acid(0.67 mL). The mixture was heated at 110° C. for 24 h. The mixture wasthen diluted with methylene chloride and washed with saturated sodiumbicarbonate. The organic layer was then dried with sodium sulfate,filtered and concentrated. The residue was purified by chromatography(silica gel, 0-5% methanol/methylene chloride) to afford ExampleCompound 138 (68 mg, 58%) as an off-white solid: ¹H NMR (500 MHz,DMSO-d₆) δ 8.29 (d, J=2.1 Hz, 1H), 7.95 (d, J=2.0 Hz, 1H), 7.37-7.33 (m,2H), 7.30-7.28 (m, 3H), 5.67 (s, 2H), 2.38 (s, 3H), 2.37-2.35 (m, 1H),2.20 (s, 3H), 1.13-1.11 (m, 4H); ESI m/z 345 [M+H]⁺. HPLC>99%.

Preparation of1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one(Example Compound 145),1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-4-nitro-1H-benzo[d]imidazol-2-amine(Example Compound 159),4-Amino-1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one(Example Compound 161) and1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N₂-ethyl-1H-benzo[d]imidazole-2,4-diamine(Example Compound 160)

Step 1: To a mixture of 32 (1.50 g, 6.46 mmol) and 3 (2.16 g, 9.70 mmol)in 1,4-dioxane (40 mL) and water (4 mL) was added potassium carbonate(1.79 g, 12.9 mmol) and tetrakis(triphenylphosphine)palladium(0) (373mg, 0.32 mmol). The reaction was stirred and heated at 90° C. for 17 h.The reaction mixture was diluted with methanol (20 mL) and silica gel(20 g) was added. The suspension was concentrated to dryness and theresulting powder was loaded onto silica gel and eluted with 0-50% ethylacetate in hexanes. The clean product was concentrated to give 87 (585mg, 36%) as a brown solid: ¹H NMR (500 MHz, CDCl₃) δ 7.62 (d, J=2.0 Hz,1H), 6.81 (d, J=2.0 Hz, 1H), 6.01 (br s, 2H), 3.52 (br s, 2H), 2.39 (s,3H), 2.25 (s, 3H).

Step 2: To a solution of 87 (250 mg, 1.01 mmol), a catalytic amount ofDMAP and 1,4-dioxane (4 mL) in a pressure tube was added1,1′-carbonyldiimidazole (327 mg, 2.01 mmol). The tube was sealed andheated to 80° C. for 17 h. The reaction mixture was diluted withmethanol (20 mL) and silica gel (10 g) was added. The suspension wasconcentrated to dryness and the resulting powder was loaded onto silicagel (40 g) and eluted with 0-70% ethyl acetate in hexanes. The cleanproduct was concentrated to give 88 (167 mg, 60%) as an orange solid: ¹HNMR (500 MHz, CDCl₃) δ 7.74 (d, J=1.5 Hz, 1H), 7.17 (d, J=1.5 Hz, 1H),2.43 (s, 3H), 2.28 (s, 3H).

Step 3: To a solution of 88 (309 mg, 1.13 mmol), potassium carbonate(312 mg, 2.25 mmol), acetonitrile (5 mL) and DMF (2 mL) in a pressuretube was added (bromomethyl)cyclopropane (183 mg, 1.35 mmol) and thereaction was sealed and heated at 80° C. for 17 h. The material wascooled to room temperature and poured into a saturated aq. NaCl solution(30 mL). Ethyl acetate (100 mL) was added and the layers were separated.The ethyl acetate layer was washed with saturated aq. NaCl solution(2×100 mL), dried over Na₂SO₄, filtered and the filtrate wasconcentrated. The resulting oil in CH₂Cl₂ (10 mL) was loaded onto silicagel (80 g) and eluted with 0-40% ethyl acetate in hexanes. The cleanproduct was then purified by reverse phase HPLC on a Polaris columneluting with 10-90% CH₃CN in H₂O and the clean fractions were frozen andlyophilized to give Example Compound 145 (88 mg, 35%) as a yellow solid:¹H NMR (500 MHz, CD₃OD) δ 7.82 (d, J=1.5 Hz, 1H), 7.52 (d, J=1.0 Hz,1H), 3.87 (d, J=7.0 Hz, 2H), 2.45 (s, 3H), 2.29 (s, 3H), 1.30-1.18 (m,1H), 0.60-0.52 (m, 2H), 0.47-0.43 (m, 2H). ESI m/z 329 [M+H]⁺. HPLC>99%.

Step 4: A solution of Example Compound 145 (171 mg, 0.521 mmol) inphosphorus(V) oxychloride (4 mL) was placed in a sealed tube and heatedat 110° C. for 8 h. The solvent was removed in vacuo and a saturated aq.NaHCO₃ solution (5 mL) was added. The mixture was extracted with ethylacetate (2×20 mL) and the combined extracts were dried over Na₂SO₄,filtered and the filtrate was concentrated. THF (5 mL) and 2.0Methylamine solution in THF were then added and the reaction was heatedat 70° C. for 12 h. The reaction was concentrated to dryness and theresidue diluted with CH₂Cl₂ (5 mL). The resulting solution was loadedonto silica gel (40 g) and eluted with 0-80% ethyl acetate in hexanes.The clean product was then purified by reverse phase HPLC on a Polariscolumn eluting with 10-90% CH₃CN in H₂O and the clean fractions werefrozen and lyophilized to give Example Compound 159 (105 mg, 57%) as ayellow solid: ¹H NMR (500 MHz, CDCl₃) δ 7.78 (d, J=1.5 Hz, 1H), 7.44 (d,J=1.5 Hz, 1H), 4.03 (d, J=6.5 Hz, 2H), 3.67 (q, J=7.0 Hz, 2H), 2.44 (s,3H), 2.29 (s, 3H), 1.33 (t, J=7.0 Hz, 3H), 1.30-1.18 (m, 1H), 0.60-0.52(m, 2H), 0.47-0.41 (m, 2H). ESI m/z 356 [M+H]⁺. HPLC>99%.

Step 5: A solution of Example Compound 145 (59 mg, 0.215 mmol) in THF(10 ml) was added a solution of sodium dithionite (225 mg, 1.29 mmol) inwater (10 mL) dropwise over 5 min. The solution was stirred at roomtemperature for 16 h and the solvents were removed in vacuo. Methanol(20 mL) was added and the suspension stirred at room temperature for 3h. The mixture was filtered and the filtrate was concentrated todryness. A solution of 2N aq. HCl (10 mL) was added to the residue andheated to reflux for 5 min. After concentration to dryness, methanol wasadded (10 mL) and the solution was adjusted to pH 8 using saturated aq.NaHCO₃ solution (15 mL). Silica gel was added (10 g) and the suspensionwas concentrated to dryness. The resulting powder was loaded onto silicagel and eluted with 0-4% methanol in methylene chloride. The cleanproduct was then purified by reverse phase HPLC on a Polaris Cig columneluting with 10-90% CH₃CN in H₂O and the clean fractions were frozen andlyophilized to give Example Compound 161 (32 mg, 50%) as a white solid:¹H NMR (500 MHz, CD₃OD) δ 6.49 (d, J=1.5 Hz, 1H), 6.42 (d, J=1.5 Hz,1H), 3.75 (d, J=6.5 Hz, 2H), 2.39 (s, 3H), 2.24 (s, 3H), 1.28-1.18 (m,1H), 0.56-0.48 (m, 2H), 0.44-0.39 (m, 2H). ESI m/z 299 [M+H]⁺. HPLC97.4%.

Step 6: A solution of Example Compound 159 (90 mg, 0.253 mmol) in THF(10 ml) was added a solution of sodium dithionite (265 mg, 1.52 mmol) inwater (10 mL) dropwise over 5 min. The solution was stirred at roomtemperature for 16 h and the solvents were removed in vacuo. Methanol(20 mL) was added and the suspension stirred at room temperature for 3h. The mixture was filtered and the filtrate was concentrated todryness. A solution of 2N aq. HCl (10 mL) was added to the residue andheated to reflux for 5 min. After concentration to dryness, methanol wasadded (10 mL) and the solution was adjusted to pH 8 using saturated aq.NaHCO₃ solution (15 mL). Silica gel was added (10 g) and the suspensionwas concentrated to dryness. The resulting powder was loaded onto silicagel and eluted with 0-4% methanol in methylene chloride. The cleanproduct was then purified by reverse phase HPLC on a Polaris Cig columneluting with 10-90% CH₃CN in H₂O and the clean fractions were frozen andlyophilized to give Example Compound 160 (61 mg, 74%) as a white solid:¹H NMR (500 MHz, CD₃OD) δ 6.49 (d, J=1.5 Hz, 1H), 6.37 (d, J=1.5 Hz,1H), 3.88 (d, J=6.5 Hz, 2H), 3.48 (q, J=7.0 Hz, 2H), 2.39 (s, 3H), 2.24(s, 3H), 1.28-1.18 (m, 1H), 0.53-0.48 (m, 2H), 0.40-0.35 (m, 2H). ESIm/z 326 [M+H]⁺. HPLC>99%.

Preparation of4-amino-6-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxybenzyl)-1H-benzo[d]imidazol-2(3H)-one(Example Compound 129)

To a solution of Example Compound 104 (54 mg, 0.15 mmol) indichloromethane (5 mL) under nitrogen atmosphere was added borontribromide (0.45 mL, 1M in dichloromethane, 0.45 mmol). The reactionmixture was stirred at room temperature overnight, treated withmethanol, and concentrated in vacuum. The residue was dissolved inmethanol, basified with ammonium hydroxide, concentrated in vacuum, andpurified by chromatography (silica gel, 0-20% methanol in ethylacetate). It was further purified by reverse phase HPLC on a Polaris Cigcolumn eluting with 10-90% CH₃CN in H₂O to give Example Compound 129 (31mg, 59%) as an off-white solid: ¹H NMR (500 MHz, CD₃OD) δ 7.17 (d, J=8.6Hz, 2H), 6.72 (d, J=8.6 Hz, 2H), 6.39 (d, J=1.3 Hz, 1H), 6.26 (d, J=1.3Hz, 1H), 4.94 (s, 2H), 2.28 (s, 3H), 2.12 (s, 3H); HPLC>99%, t_(R)=11.0min; ESI m/z 351 [M+H]⁺.

Preparation of1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-ol(Example Compound 173)

Step 1: To a solution of 89 (5.00 g, 32.5 mmol) and triethylamine (9.04mL, 65.0 mmol) in N,N-dimethylformamide (150 mL) was addedtert-butylchlorodimethylsilane (5.86 g, 39.0 mmol) at room temperature.The reaction mixture was stirred at room temperature for 1 h and dilutedwith ethyl acetate. The mixture was washed with water, brine, dried oversodium sulfate, and filtered. The filtrate was concentrated to afford 90(8.59 g, 98%) as a brown oil: ¹H NMR (300 MHz, CDCl₃) δ 7.75 (dd, J=1.3,8.9 Hz, 1H), 6.89 (dd, J=1.2, 7.6 Hz, 1H), 6.53 (dd, J=8.8, 7.6 Hz, 1H),6.45-6.15 (bs, 2H), 1.03 (s, 9H), 0.28 (s, 6H).

Step 2: To a solution of 90 (8.59 g, 32.1 mmol) in acetic acid (120 mL)was added N-bromosuccinimide (6.28 g, 35.3 mmol) at room temperature.The reaction mixture was stirred at room temperature for 30 min and thenconcentrated. The residue was dissolved in methanol and basified with 5%aqueous sodium bicarbonate. The precipitate formed was filtered, washedwith water, and dried under vacuum to afford 91 (8.56 g, 76%) as anorange solid: ¹H NMR (500 MHz, CDCl₃) δ 7.91 (d, J=2.1 Hz, 1H), 6.96 (d,J=2.1 Hz, 1H), 6.50-6.12 (bs, 2H), 1.03 (s, 9H), 0.30 (s, 6H).

Step 3: To a solution of 91 (5.00 g, 14.4 mmol) in tetrahydrofuran (60mL) was added platinum on carbon (1.00 g, 5% Pt on carbon). The reactionmixture was stirred under hydrogen atmosphere at room temperatureovernight. The mixture was filtered, washed with MeOH, and the filtratewas concentrated to afford 92 (5.65 g, >99%) as a dark brown oil: ¹H NMR(500 MHz, CDCl₃) δ 6.51 (d, J=2.0 Hz, 1H), 6.46 (d, J=2.0 Hz, 1H),3.50-2.50 (bs, 4H), 1.01 (s, 9H), 0.24 (s, 6H); ESI m/z 317 [M+H]⁺.

Step 4: To a solution of 92 (2.00 g, 6.31 mmol) in ethanol (50 mL) wasadded triethylorthoacetate (3.07 g, 18.9 mmol) and sulfamic acid (1 mg,0.01 mmol). The reaction was heated in a sealed tube at 80° C.overnight. The mixture was concentrated and purified by chromatography(silica gel, 0-100% ethyl acetate in hexanes) to afford 93 (2.07 g, 96%)as a light red solid: ¹H NMR (500 MHz, CDCl₃) δ 8.75 (s, 1H), 7.45 (s,1H), 6.78 (s, 1H), 3.61 (s, 3H), 1.03 (s, 9H), 0.28 (s, 6H); ESI m/z 341[M+H]⁺.

Step 5: A mixture of 93 (200 mg, 0.587 mmol), benzyl bromide (150 mg,0.880 mmol), and potassium bicarbonate (113 mg, 0.822 mmol) inacetonitrile (20 mL) was heated at 45° C. for 2 days. The reactionmixture was cooled to room temperature, concentrated and purified bychromatography (silica gel, 0-30% ethyl acetate in hexanes) to afford 94(303 mg, 30%) as a brown solid: ¹H NMR (500 MHz, CDCl₃) δ 7.36-7.26 (m,3H), 7.01 (d, J=8.2 Hz, 2H), 6.97 (d, J=1.6 Hz, 1H), 6.81 (d, J=1.6 Hz,1H), 5.22 (s, 2H), 2.50 (s, 3H), 1.05 (s, 9H), 0.30 (s, 6H); ESI m/z 431[M+H]⁺.

Step 6: To a solution of 94 (75 mg, 0.17 mmol) in 1,4-dioxane (10 mL)and water (1 mL) was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(58 mg, 0.26 mmol), potassium bicarbonate (70 mg, 0.70 mmol), andtetrakis(triphenylphosphine)palladium(0) (10 mg, 0.0087 mmol). Thereaction mixture was purged with nitrogen and heated at 90° C. for 2 h.The reaction mixture was cooled to room temperature, concentrated andpurified by chromatography (silica gel, 0-100% ethyl acetate in hexanes)to give 95 (53 mg, 70%) as an off-white solid: ¹H NMR (500 MHz, CD₃OD) δ7.33 (t, J=6.3 Hz, 2H), 7.27 (t, J=5.1 Hz, 1H), 7.14 (d, J=7.1 Hz, 2H),6.89 (d, J=1.3 Hz, 1H), 6.58 (d, J=1.3 Hz, 1H), 5.45 (s, 2H), 2.59 (s,3H), 2.32 (s, 3H), 2.16 (s, 3H), 1.05 (s, 9H), 0.30 (s, 6H); HPLC>99%,t_(R)=16.4 min; ESI m/z 448 [M+H]⁺.

Step 7: A mixture of 95 (48 mg, 0.11 mmol) and potassium carbonate (30mg, 0.22 mmol) in acetonitrile (10 mL) was heated in a sealed tube at80° C. overnight. The reaction mixture was cooled to room temperature,concentrated and purified by chromatography (silica gel, 0-20% methanolin ethyl acetate). It was further purified by reverse phase HPLC on aPolaris Cig column eluting with 10-90% CH₃CN in H₂O to give ExampleCompound 173 (32 mg, 87%) as an off-white solid: ¹H NMR (500 MHz,DMSO-d₆) δ 9.84 (s, 1H), 7.33 (t, J=7.6 Hz, 2H), 7.26 (t, J=7.3 Hz, 1H),7.18 (d, J=7.1 Hz, 2H), 6.86 (d, J=1.3 Hz, 1H), 6.47 (d, J=1.3 Hz, 1H),5.42 (s, 2H), 2.52 (s, 3H), 2.33 (s, 3H), 2.15 (s, 3H); ESI m/z 334[M+H]⁺.

Preparation of4-Amino-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazole-2(3H)-thione(Example Compound 177)

A mixture of Example Compound 16 (34 mg, 0.10 mmol) and Lawesson'sreagent (202 mg, 0.5 mmol) was heated to 180° C. in microwave reactorfor 2 h. The mixture was concentrated, the residue was purified bychromatography (silica gel, 0-40% EtOAc/hexanes) followed bychromatography (C₁₈, 10-70% CH₃CN/water) to give Example Compound 177(13 mg, 37%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 12.56(s, 1H), 7.45-7.42 (m, 2H), 7.34-7.25 (m, 3H), 6.44 (d, J=1.2 Hz, 1H),6.39 (d, J=1.5 Hz, 1H), 5.44 (s, 4H), 2.29 (s, 3H), 2.11 (s, 3H); ESIm/z 351 [M+H]⁺. HPLC 98.6%

Preparation of1-benzyl-3-methyl-6-(1-methyl-1H-pyrazol-5-yl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one(Example Compound 198) and4-amino-1-benzyl-3-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-2(3H)-one(Example Compound 199)

Compound 96 was prepared by following the similar method for thepreparation of Example Compound 15 usingl-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

Step 1: A mixture of 96 (70 mg, 0.20 mmol), CH₃I (85 mg, 0.60 mmol) andK₂CO₃ (110 mg, 0.8 mmol) in DMF (3 mL) was stirred at rt for 16 h. Thereaction mixture was diluted with EtOAc (100 mL) and washed with brine(3×50 mL). The organic layer was dried over sodium sulfate, filtered andconcentrated. The residue was purified by chromatography (silica gel,20-70% ethyl acetate/hexanes) to afford Example Compound 198 (50 mg,68%) as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 7.66 (d, J=1.5 Hz,1H), 7.50 (d, J=1.8 Hz, 1H), 7.36-7.30 (m, 5H), 7.02 (d, J=1.5 Hz, 1H),6.27 (d, J=1.2 Hz, 1H), 5.16 (s, 2H), 3.69 (s, 3H), 3.65 (s, 3H); ESIm/z 364 [M+H]⁺.

Step 2: To a solution of Example Compound 198 (45 mg, 0.12 mmol) in THF(5 mL) and water (4 mL) was added Na₂S₂O₄ (129 mg, 0.74 mmol). Themixture was stirred at rt for 4 h, 2N HCl (1 mL) was added, the mixturewas heated to reflux for 15 minutes then cooled to rt. Na₂CO₃ was addedslowly to adjust to pH 9. The mixture was extracted with CH₂Cl₂ (100mL), the organic layer was washed with brine (50 mL), filtered,concentrated and purified by chromatography (silica gel, 0-10%methanol/ethyl acetate) to afford Example Compound 199 (37 mg, 90%) as awhite solid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.39 (d, J=1.8 Hz, 1H),7.35-7.24 (m, 5H), 6.56 (d, J=1.5 Hz, 1H), 6.54 (d, J=1.5 Hz, 1H), 6.20(d, J=1.8 Hz, 1H), 5.15 (s, 2H), 5.01 (s, 2H), 3.72 (s, 3H), 3.63 (s,3H); ESI m/z 334 [M+H]⁺.

Preparation of4-(1-benzyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole(Example Compound 220)

To a solution of 28 (100 mg, 0.34 mmol) andtetrahydro-2H-pyran-4-carboxylic acid (65 mg, 0.51 mmol) in CH₂Cl₂ wasadded EDC (131 mg, 0.68 mmol), i-Pr₂NEt (132 mg, 1.02 mmol) and DMAP (10mg). The reaction mixture was stirred at rt for 16 h. The mixture wasdiluted with EtOAc (100 mL), washed with brine (50 mL) and saturatedNaHCO₃ (50 mL). The organic layer was dried over sodium sulfate,filtered and concentrated. The residue was dissolved in AcOH (2 mL) andheated to reflux for 5 h. The mixture was concentrated, the residue wasdissolved in EtOAc (100 mL), washed with saturated NaHCO₃ (2×50 mL) andbrine (50 mL). The organic layer was dried over sodium sulfate, filteredand concentrated. The residue was purified by chromatography (silicagel, 0-10% MeOH/EtOAc) to give Example Compound 220 (47 mg, 36%) as alight brown solid: ¹H NMR (300 MHz, CDCl₃) δ 8.41 (d, J=1.8 Hz, 1H),7.38-7.32 (m, 3H), 7.24 (d, J=2.1 Hz, 1H), 7.08-7.05 (m, 2H), 5.42 (s,2H), 4.12 (dd, J=11.7, 1.8 Hz, 2H), 3.52 (td, J=11.7, 1.8 Hz, 2H),3.20-3.12 (m, 1H), 2.36-2.23 (m, 5H), 2.14 (s, 3H), 1.83-1.78 (m, 2H);ESI m/z 389 [M+H]⁺.

Preparation of1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-methyl-1H-imidazo[4,5-b]pyridine-2-carboxamide(Example Compound 221)

A mixture of 28 (300 mg, 1.02 mmol) and methyl 2,2,2-trimethoxyacetate(1.5 mL) was heated to 120° C. for 16 h. The mixture was purified bychromatography (silica gel, 20-80% EtOAc/hexanes) to give a brown solid.The solid was dissolved in CH₃NH₂/THF (2 M) (3 mL) and heated 80° C. for16 h. The mixture was concentrated, the residue was purified bychromatography (C₁₈, 10-70% CH₃CN/water) to give Example Compound 221(45 mg, 12%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.31 (q,J=4.5 Hz, 1H), 8.27 (d, J=1.8 Hz, 1H), 7.54 (d, J=1.8 Hz, 1H), 7.36-7.24(m, 5H), 5.54 (s, 2H), 3.00 (d, J=4.8 Hz, 3H), 2.21 (s, 3H), 2.00 (s,3H); ESI m/z 362 [M+H]⁺.

Preparation of1-benzyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one(Example Compound 171)

Step 1: To a solution of 85 (1.14 g, 4.09 mmol) in 1,4-dioxane (41 mL)was added 1,1′-carbonyldiimidazole (796 mg, 4.91 mmol). The reactionmixture was heated at 110° C. for 16 h. The reaction mixture wasconcentrated. Purification by chromatography (silica gel, 0-100% ethylacetate/hexanes) afforded 97 (1.03 g, 83%) as a white solid: ¹H NMR (500MHz, DMSO-d₆) δ 11.89 (s, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.68 (d, J=2.0Hz, 1H), 7.37-7.32 (m, 4H), 7.30-7.26 (m, 1H), 5.02 (s, 2H).

Step 2: To a solution of 97 (334 mg, 1.09 mmol) in 1,4-dioxane (11 mL)was added 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (457 mg,2.20 mmol), sodium carbonate (1.0 M in H₂O, 3.29 mL, 3.29 mmol) andtetrakis(triphenylphosphine)palladium(0) (127 mg, 0.1 mmol). Thereaction mixture was purged with nitrogen and heated at 90° C. for 32 h.The mixture was diluted with methylene chloride (80 mL), washed withbrine (40 mL), dried over sodium sulfate, filtered and concentrated. Theresidue was purified by chromatography (silica gel, 0-5%methanol/methylene chloride) followed by trituration with EtOAc toafford Example Compound 171 (173 mg, 52%) as a white solid: ¹H NMR (500MHz, DMSO-d₆) δ 11.87 (s, 1H), 8.04 (d, J=1.5 Hz, 1H), 7.57 (d, J=1.5,1H), 7.46 (d, J=2.0 Hz, 1H), 7.38 (d, J=7.5 Hz, 2H), 7.34 (t, J=7.5 Hz,2H), 7.27 (t, J=7.0 Hz, 1H), 6.37 (d, J=1.5 Hz, 1H), 5.06 (s, 2H), 3.77(s, 3H); ESI m/z 306 [M+H]⁺.

Preparation ofN-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamide(Example Compound 99)

A solution of Example Compound 39 (100 mg, 0.29 mmol) in EtOH (3 mL) andAcOH (1 mL) was added iron powder (162 mg, 2.9 mmol). The reactionmixture was heated at 80° C. for 1 h. It was filtered through a layer ofCelite and the filtrate was concentrated. Purification by chromatography(silica gel, 0-5% methanol/dichloromethane) afforded Example Compound 99(28 mg, 27%) as a red solid: ¹H NMR (300 MHz, DMSO-d₆) δ 10.2 (s, 1H),8.32 (d, J=1.8 Hz, 1H), 8.23 (s, 1H), 7.97 (d, J=1.8 Hz, 1H), 7.32-7.25(m, 5H), 5.45 (s, 2H), 2.40 (s, 3H), 2.22 (s, 3H), 2.12 (s, 3H); ESI MSm/z 361 [M+H]⁺.

Preparation of1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-amine(Example Compound 100)

To a solution of Example Compound 39 (100 mg, 0.29 mmol) in EtOH (3 mL)and H₂SO₄ (0.5 mL) was added iron powder (162 mg, 2.9 mmol). Thereaction mixture was heated at 80° C. for 1 h. It was diluted with EtOH(20 mL), adjusted to pH 7 by 6 N aq. NaOH. The mixture was filteredthrough a layer of Celite and the filtrate was concentrated.Purification by chromatography (silica gel, 0-5%methanol/dichloromethane) afforded Example Compound 100 (12 mg, 13%) asa red solid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.18 (d, J=1.8 Hz, 1H), 7.82(d, J=1.8 Hz, 1H), 7.33-7.21 (m, 5H), 7.06 (s, 1H), 5.30 (s, 2H), 4.26(s, 2H), 2.37 (s, 3H), 2.21 (s, 3H); ESI MS m/z 319 [M+H]⁺.

Preparation of4-benzyl-6-(3,5-dimethylisoxazol-4-yl)-3,4-dihydroquinoxalin-2(1H)-one(Example Compound 156)

Step 1: 4-Bromo-2-fluoro-1-nitrobenzene (1.00 g, 4.54 mmol), ethyl2-(benzylamino)acetate (0.87 g, 4.5 mmol), and potassium carbonate (0.78g, 5.7 mmol) in ethanol (15 mL) and water (11 mL) were heated at 85° C.for 10 h then stirred at rt for 8 h. The reaction mixture was dilutedwith water and brine then washed with methylene chloride. The resultantaqueous layer was filtered to afford 99 as an orange solid (1.28 g,72%): ¹H NMR (300 MHz, DMSO-d₆): δ 7.57 (d, J=8.6 Hz, 1H), 7.37-7.21 (m,6H), 6.97 (dd, J=8.7, 2.0 Hz, 1H), 4.52 (s, 2H), 3.40 (s, 2H).

Step 2: To a solution of 99 (1.28 g, 3.51 mmol) in acetic acid (14 mL)at rt was added iron (470 mg, 8.4 mmol) and the resultant slurry washeated to 90° C. for 2.25 h. The mixture was cooled to rt and filteredthrough Celite, rinsing with methylene chloride. The filtrate wasconcentrated in vacuo and the resultant oil was partitioned betweenmethylene chloride and saturated aqueous sodium bicarbonate. The aqueouslayer was extracted with methylene chloride and the combined organiclayers were dried with sodium sulfate, concentrated in vacuo, andpurified by flash column chromatography (silica gel, 0-100% ethylacetate/methylene chloride) to afford 100 as a white solid (430 mg, 39%yield): ¹H NMR (300 MHz, CDCl₃) δ 8.74 (br s, 1H), 7.39-7.26 (m, 5H),6.89-6.85 (m, 2H), 6.62 (d, J=8.0 Hz, 2H), 4.39 (s, 2H), 3.80 (s, 2H).

Step 3: Using the similar procedure used for Example Compound 7 step 1on compound 100 afforded Example Compound 156 as a white solid: ¹H NMR(500 MHz, DMSO-d₆) δ 10.58 (s, 1H), 7.38-7.34 (m, 4H), 7.30-7.23 (m,1H), 6.87 (d, J=7.9 Hz, 1H), 6.65 (d, J=7.9 Hz, 1H), 6.51 (s, 1H), 4.46(s, 2H), 3.86 (s, 2H), 2.15 (s, 3H), 1.97 (s, 3H); ESI m/z 334 [M+H]⁺.

Preparation of4-benzyl-6-(1-methyl-1H-pyrazol-5-yl)-3,4-dihydroquinoxalin-2(1H)-one(Example Compound 166)

Using the similar procedure used for Example Compound 7 step 1 oncompound 100 afforded Example Compound 166 as a white solid: ¹H NMR (500MHz, DMSO-d₆) δ 10.62 (s, 1H), 7.37-7.33 (m, 5H), 7.29-7.25 (m, 1H),6.90 (d, J=7.9 Hz, 1H), 6.80 (dd, J=7.9, 1.8 Hz, 1H), 6.70 (d, J=1.6 Hz,1H), 6.18 (d, J=1.8 Hz, 1H), 4.49 (s, 2H), 3.83 (s, 2H), 3.58 (s, 3H);ESI m/z 319 [M+H]⁺.

Preparation of(R)-4-benzyl-6-(3,5-dimethylisoxazol-4-yl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one(Example Compound 174)

Step 1: 4-Bromo-2-fluoro-1-nitrobenzene (0.50 g, 2.3 mmol), (R)-methyl2-(benzylamino)propanoate (0.55 g, 2.3 mmol), and potassium carbonate(0.47 g, 3.4 mmol) in ethanol (8 mL) and water (6 mL) were heated at 85°C. for 10 h then stirred at rt for 8 h. The reaction mixture was dilutedwith water and filtered. The pH of the filtrate was adjusted to 4 with6N aqueous HCl and the resultant slurry was re-filtered to afford 101 asa sticky orange solid (not weighed; used directly in the next step).

Step 2: Using the similar procedure used for Example Compound 156 step 2on compound 101 afforded compound 102 as a white solid (430 mg, 39%yield): ¹H NMR (500 MHz, DMSO-d₆) δ 10.57 (br s, 1H), 7.39-7.25 (m, 5H),6.87-6.66 (m, 3H), 4.60 (d, J=15.5 Hz, 1H), 4.29 (d, J=15.2 Hz, 1H),3.85 (q, J=6.9 Hz, 1H), 1.08 (d, J=6.7 Hz, 3H).

Step 3: Using the similar procedure used for Example Compound 156 step 3on compound 102 afforded Example Compound 174 as an off-white solid: ¹HNMR (500 MHz, DMSO-d₆) δ 10.53 (s, 1H), 7.37-7.32 (m, 4H), 7.26-7.23 (m,1H), 6.88 (d, J=7.9 Hz, 1H), 6.66 (dd, J=7.9, 1.7 Hz, 1H), 6.42 (d,J=1.5 Hz, 1H), 4.54 (d, J=15.6 Hz, 1H), 4.37 (d, J=15.7 Hz, 1H), 3.98(q, J=6.7 Hz, 1H), 2.11 (s, 3H), 1.93 (s, 3H), 1.12 (d, J=6.7 Hz, 3H);ESI m/z 348 [M+H]⁺.

Preparation of1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one(Example Compound 118) and1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-1H-imidazo[4,5-b]pyridin-2-amine(Example Compound 131)

Step 1: To a stirred solution of 26 (2.00 g, 10.6 mmol) in dry CH₂Cl₂(50 mL) was added glacial acetic acid (0.61 mL, 10.8 mmol) andcyclopropanecarboxaldehyde (0.81 mL, 12.3 mmol). The solution wasstirred at room temperature for 1 h and was cooled to 0° C. Sodiumborohydride (1.21 g, 31.8 mmol) was added carefully and the reaction wasallowed to warm to room temperature. After stirring at ambienttemperature for 15 h, saturated aq. NaHCO₃ (20 mL) was added to basifyand then the mixture was extracted with CH₂Cl₂ (2×100 mL). The combinedmethylene chloride layers were dried over Na₂SO₄, filtered and thefiltrate was concentrated to a brown residue. The residue was dilutedwith CH₂Cl₂ (20 mL), the solution was loaded onto silica gel (120 g) andeluted with 0-70% ethyl acetate in hexanes to afford 103 (330 mg, 13%)as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 7.62 (d, J=2.0 Hz, 1H),6.83 (d, J=1.5 Hz, 1H), 4.17 (br s, 2H), 3.39 (br s, 1H), 2.90 (d, J=5.0Hz, 1H), 2.89 (d, J=5.0 Hz, 1H), 1.19-1.07 (m, 1H), 0.63-0.56 (m, 2H),0.27-0.22 (m, 2H).

Step 2: To a mixture of 103 (300 mg, 1.24 mmol) and 3 (415 mg, 1.86mmol) in 1,4-dioxane (10 mL) and water (2.5 mL) was added potassiumcarbonate (343 mg, 2.48 mmol) andtetrakis(triphenylphosphine)palladium(0) (76 mg, 0.062 mmol). Thereaction was stirred and heated at 90° C. for 17 h. The mixture wasdiluted with methanol (20 mL) and silica gel (10 g) was added. Thesuspension was concentrated to dryness and the resulting powder wasloaded onto silica gel (80 g) and eluted with 0-80% ethyl acetate inhexanes. The clean product was concentrated to give 104 (312 mg, 97%) asa yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 7.48 (d, J=1.5 Hz, 1H), 6.61(d, J=1.5 Hz, 1H), 4.27 (br s, 2H), 3.39 (br s, 1H), 2.92 (t, J=6.0 Hz,2H), 2.38 (s, 3H), 2.24 (s, 3H), 1.18-1.09 (m, 1H), 0.63-0.56 (m, 2H),0.28-0.22 (m, 2H).

Step 3: To a solution of 104 (310 mg, 1.20 mmol), a catalytic amount ofDMAP and 1,4-dioxane (4 mL) in a pressure tube was added1,1′-carbonyldiimidazole (390 mg, 2.40 mmol). The tube was sealed andheated to 80° C. for 2 h. The reaction mixture was diluted with methanol(20 mL) and silica gel (10 g) was added. The suspension was concentratedto dryness and the resulting powder was loaded onto silica gel (40 g)and eluted with 0-80% ethyl acetate in hexanes. The clean product wasconcentrated to give1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one(275 mg, 81%) as a yellow solid. A 50 mg sample was then purified byreverse phase HPLC on a Polaris Cig column eluting with 10-90% CH₃CN inH₂O and the clean fractions were frozen and lyophilized to give ExampleCompound 118 (37 mg) as a white solid: ¹H NMR (500 MHz, CD₃OD) δ 7.90(d, J=1.5 Hz, 1H), 7.50 (d, J=1.5 Hz, 1H), 3.81 (d, J=7.0 Hz, 2H), 2.42(s, 3H), 2.26 (s, 3H), 1.31-1.20 (m, 1H), 0.60-0.53 (m, 2H), 0.44-0.38(m, 2H); ESI m/z 285 [M+H]⁺.

Step 4: A solution of Example Compound 118 (220 mg, 0.774 mmol) inphosphorus(V) oxychloride (3 mL) was placed in a sealed tube and heatedat 110° C. for 6 h. The solvent was removed in vacuo and a saturated aq.NaHCO₃ solution (5 mL) was added. The mixture was extracted with ethylacetate (2×20 mL) and the combined extracts were dried over Na₂SO₄,filtered and the filtrate was concentrated. THF (5 mL) and 2.0 Methylamine solution in THF (6 mL, 12.0 mmol) were then added and thereaction was heated at 70° C. for 17 h. The reaction was concentrated todryness and the residue diluted with CH₂Cl₂ (5 mL). The resultingsolution was loaded onto silica gel (40 g) and eluted with 0-80% ethylacetate in hexanes. The clean product was then purified by reverse phaseHPLC on a Polaris column eluting with 10-90% CH₃CN in H₂O and the cleanfractions were frozen and lyophilized to give Example Compound 131 (91mg, 38%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 7.93 (d, J=2.0 Hz,1H), 7.48 (d, J=1.5 Hz, 1H), 3.98 (d, J=6.5 Hz, 2H), 3.57 (q, J=7.0 Hz,2H), 2.42 (s, 3H), 2.26 (s, 3H), 1.30 (t, J=7.0 Hz, 3H), 1.29-1.19 (m,1H), 0.59-0.52 (m, 2H), 0.45-0.39 (m, 2H); ESI m/z 312 [M+H]⁺.

Preparation of4-(1-(cyclohexylmethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole(Example Compound 191),4-(1-(cyclopentylmethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole(Example Compound 192) and4-(1-(cyclobutylmethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole(Example Compound 193)

Step 1: A mixture of 2,3-diamino-5-bromopyridine (10.0 g, 0.053 mol),cyclohexanecarboxaldehyde (6.08 g, 0.054 mol) and glacial acetic acid(3.05 mL) in dry CH₂Cl₂ (250 mL) was stirred for 1.5 h at roomtemperature. Sodium borohydride (6.06 g, 0.159 mol) was addedportionwise over 20 min and the mixture was stirred for 17 h at roomtemperature. Saturated aq. NaHCO₃ was added until the mixture reached pH8 (70 mL) and the aqueous layer extracted with CH₂Cl₂ (100 mL). Thecombined CH₂Cl₂ layers were combined, washed with water (500 mL), driedover Na₂SO₄, filtered and concentrated. The brown solid was taken up inmethanol (100 mL) and silica gel (40 g) was added. The suspension wasconcentrated to dryness and the material was purified by chromatography(silica gel, 0-50% EtOAc/hexane then 0-10% EtOAc/CH₂Cl₂) to afford 105a(1.30 g, 9%) as a brown-gray solid: ¹H NMR (500 MHz, CDCl₃) δ 7.60 (d,J=2.0 Hz, 1H), 6.85 (d, J=2.0 Hz, 1H), 4.11 (br s, 2H), 3.28 (br s, 1H),2.88 (d, J=5.0 Hz, 2H), 1.88-1.64 (m, 4H), 1.70-1.52 (m, 1H), 1.38-1.15(m, 4H), 1.10-0.96 (m, 2H).

105b was prepared starting with cyclopentanecarbaldehyde (14% yield;brown-gray solid): ¹H NMR (500 MHz, CDCl₃) δ 7.60 (d, J=2.0 Hz, 1H),6.86 (d, J=2.0 Hz, 1H), 4.14 (br s, 2H), 3.28 (br s, 1H), 2.99-2.93 (m,2H), 2.23-2.11 (m, 1H), 1.88-1.71 (m, 2H), 1.70-1.53 (m, 4H), 1.32-1.23(m, 2H).

105c was prepared starting with cyclobutanecarbaldehyde (15% yield;brown-gray solid): ¹H NMR (500 MHz, CDCl₃) δ 7.61 (d, J=2.0 Hz, 1H),6.86 (d, J=2.0 Hz, 1H), 4.12 (br s, 2H), 3.14 (br s, 1H), 3.09-3.02 (m,2H), 2.67-2.52 (m, 1H), 2.18-2.11 (m, 2H), 2.07-1.86 (m, 2H), 1.80-1.71(m, 2H).

Step 2: To a mixture of 105a (500 mg, 1.76 mmol),3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(589 mg, 2.64 mmol), potassium carbonate (487 mg, 3.52 mmol), water (4mL) and 1,4-dioxane (16 mL) was addedtetrakis(triphenylphosphine)palladium (0) and the mixture was heated to90° C. for 17 h. The two phase mixture was diluted with methanol (20 mL)and silica gel was added. After concentrating to dryness the materialwas purified by chromatography (silica gel, 0-80% EtOAc/hexane) toafford 106a (551 mg, 99%) as a brown solid: ¹H NMR (500 MHz, CDCl₃) δ7.47 (d, J=2.0 Hz, 1H), 6.62 (d, J=2.0 Hz, 1H), 4.25 (br s, 2H), 3.34(br s, 1H), 2.92 (t, J=6.0 Hz, 2H), 2.38 (s, 3H), 2.25 (s, 3H),1.88-1.67 (m, 4H), 1.67-1.56 (m, 1H), 1.33-1.19 (m, 4H), 1.10-0.96 (m,2H).

106b was prepared starting with 105b (96% yield; brown-gray solid): ¹HNMR (500 MHz, CDCl₃) δ 7.47 (d, J=1.5 Hz, 1H), 6.64 (d, J=1.5 Hz, 1H),4.25 (brs, 2H), 3.28 (br s, 1H), 2.99 (t, J=6.0 Hz, 1H), 2.38 (s, 3H),2.24 (s, 3H), 2.24-2.17 (m, 1H), 1.90-1.81 (m, 2H), 1.72-1.55 (m, 4H),1.38-1.22 (m, 2H).

106c was prepared starting with 105c (95% yield; brown-gray solid): ¹HNMR (500 MHz, CDCl₃) δ 7.65 (d, J=1.5 Hz, 1H), 6.64 (d, J=2.0 Hz, 1H),4.26 (brs, 2H), 3.18 (brs, 1H), 3.09 (t, J=6.0 Hz, 1H), 2.67-2.58 (m,1H), 2.20-2.12 (m, 2H), 2.02-1.86 (m, 2H), 1.82-1.72 (m, 2H).

Step 3: A solution of 106a (100 mg, 0.33 mmol), triethylorthoacetate (5mL) and glacial acetic acid (0.10 mL) was heated in a sealed tube for 24hours at 80° C. The mixture was evaporated to dryness and methanol (10mL), saturated aq. NaHCO₃ (5 ml) and silica gel (10 g) were added. Afterconcentrating to dryness the resulting powder was loaded onto silica geland eluted with 0-5% methanol in methylene chloride. The clean productwas then purified by reverse phase HPLC on a Polaris column eluting with10-90% CH₃CN in H₂O and the clean fractions were frozen and lyophilizedto give Example Compound 191 (56 mg, 52%) as a white solid: ¹H NMR (500MHz, CD₃OD) δ 8.30 (d, J=1.5 Hz, 1H), 7.96 (d, J=2.0 Hz, 1H), 4.14 (d,J=7.5 Hz, 2H), 2.69 (s, 3H), 2.44 (s, 3H), 2.28 (s, 3H), 1.95-1.82 (m,1H), 1.76-1.50 (m, 5H), 1.29-1.07 (m, 5H); ESI m/z 325 [M+H]⁺.

Starting with 106b, Example Compound 192 (31 mg, 29%) was prepared as awhite solid: ¹H NMR (500 MHz, CD₃OD) δ 8.30 (d, J=2.0 Hz, 1H), 7.98 (d,J=2.0 Hz, 1H), 4.26 (d, J=8.0 Hz, 2H), 2.71 (s, 3H), 2.49-2.38 (m, 1H),2.44 (s, 3H), 2.28 (s, 3H), 1.80-1.68 (m, 4H), 1.66-1.57 (m, 2H),1.40-1.27 (m, 2H); ESI m/z 311 [M+H]⁺.

Starting with 106c, Example Compound 193 (33 mg, 30%) was prepared as awhite solid: ¹H NMR (500 MHz, CD₃OD) δ 8.30 (d, J=1.5 Hz, 1H), 8.00 (d,J=1.5 Hz, 1H), 4.33 (d, J=7.0 Hz, 2H), 2.92-2.80 (m, 1H), 2.70 (s, 3H),2.45 (s, 3H), 2.28 (s, 3H), 2.10-1.98 (m, 2H), 1.96-1.81 (m, 4H); ESIm/z 297 [M+H]⁺.

Preparation of1-(cyclopentylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one(Example Compound 202) and1-(cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one(Example Compound 203)

A solution of 106b (1.30 g, 4.54 mmol), 1,1′-carbonyldiimidazole (1.47g) and N,N-dimethylaminopyridine (5 mg) in 1,4-dioxane (16 mL) washeated at 80° C. for 2 h and cooled to room temperature. To the mixturewas added silica gel (10 g) and methanol (20 mL) and the suspension wasconcentrated to a dry powder. This material was loaded onto silica gel(80 g) and eluted with 0-90% ethyl acetate in hexanes to give 1.08 g(76%) of Example Compound 202 as a yellow solid. A 100 mg sample of theproduct was then purified by reverse phase HPLC on a Polaris columneluting with 10-90% CH₃CN in H₂O and the clean fractions were frozen andlyophilized to give Example Compound 202 as a white solid: ¹H NMR (500MHz, CD₃OD) δ 7.90 (d, J=1.5 Hz, 1H), 7.47 (d, J=2.0 Hz, 1H), 3.86 (d,J=7.5 Hz, 2H), 2.52-2.38 (m, 1H), 2.41 (s, 3H), 2.25 (s, 3H), 1.78-1.68(m, 4H), 1.60-1.52 (m, 2H), 1.41-1.30 (m, 2H); ESI m/z 313 [M+H]⁺.

Starting with 106c, Example Compound 203 (76% yield, white solid) wassynthesized in a similar procedure as Example Compound 202: ¹H NMR (500MHz, CD₃OD) δ 7.89 (d, J=1.5 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 3.94 (d,J=7.0 Hz, 2H), 2.86-2.77 (m, 1H), 2.41 (s, 3H), 2.25 (s, 3H), 2.08-1.98(m, 2H), 1.94-1.80 (m, 4H); ESI m/z 299 [M+H]⁺.

Preparation of4-(1-(cyclopentylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)morpholine(Example Compound 208) and4-(2-(azetidin-1-yl)-1-(cyclopentylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole(Example Compound 209)

A solution of Example Compound 202 (175 mg, 0.56 mmol) and phosphorus(V)oxychloride (4 mL) was heated to 110° C. for 17 h. The reaction wasconcentrated in vacuo and saturated aq. NaHCO₃ (5 mL) and ethyl acetate(20 mL) were added. The ethyl acetate layer was separated, dried overNa₂SO₄, filtered and the filtrate was concentrated to a dark yellowsolid. The solid was dissolved in THF (5 mL) and morpholine (732 mg,8.40 mmol) was added. The stirred solution was heated to 70° C. for 17h. To the cooled mixture was added silica gel (5 g) and methanol (20 mL)and the suspension was concentrated to a dry powder. This material wasloaded onto silica gel (40 g) and eluted with 0-3% methanol in methylenechloride to give 143 mg (67%) of product as an off-white solid. Theproduct sample was then purified by reverse phase HPLC on a Polariscolumn eluting with 10-90% CH₃CN in H₂O and the clean fractions werefrozen and lyophilized to give Example Compound 208 as a white solid: ¹HNMR (500 MHz, CD₃OD) δ 8.17 (d, J=1.5 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H),4.14 (d, J=7.5 Hz, 2H), 3.87 (t, J=5.0 Hz, 4H), 3.41 (t, J=5.0 Hz, 4H),2.58-2.49 (m, 1H), 2.43 (s, 3H), 2.27 (s, 3H), 1.75-1.66 (m, 2H),1.62-1.50 (m, 4H), 1.30-1.19 (m, 2H). ESI m/z 382 [M+H]⁺.

Example Compound 209 was synthesized using a similar procedure as wasused for Example Compound 208; Example Compound 209 was collected as awhite solid (166 mg, 84%): ¹H NMR (500 MHz, CD₃OD) δ 8.00 (d, J=1.5 Hz,1H), 7.59 (d, J=1.5 Hz, 1H), 4.42-4.37 (m, 4H), 4.01 (d, J=8.0 Hz, 2H),2.57-2.44 (m, 2H), 2.50-2.41 (m, 1H), 2.41 (s, 3H), 2.25 (s, 3H),1.76-1.51 (m, 6H), 1.32-1.22 (m, 2H). ESI m/z 352 [M+H]⁺.

Preparation of4-(1-(cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)morpholine(Example 210) and4-(2-(azetidin-1-yl)-1-(cyclobutylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole(Example 211)

Example 210 and Example 211 were synthesized using a similar procedureas was used for Example 208.

Example 210 collected as white solid (176 mg, 82% yield): ¹H NMR (500MHz, CD₃OD) δ 8.16 (d, J=1.5 Hz, 1H), 7.80 (d, J=2.0 Hz, 1H), 4.24 (d,J=7.0 Hz, 2H), 3.88 (t, J=5.0 Hz, 4H), 3.41 (t, J=5.0 Hz, 4H), 2.93-2.82(m, 1H), 2.43 (s, 3H), 2.27 (s, 3H), 1.98-1.91 (m, 2H), 1.90-1.76 (m,4H). ESI m/z 368 [M+H]⁺.

Example 211 collected as white solid (180 mg, 91% yield): ¹H NMR (500MHz, CD₃OD) δ 7.99 (d, J=2.0 Hz, 1H), 7.61 (d, J=2.0 Hz, 1H), 4.38 (m,4H), 4.10 (d, J=7.0 Hz, 2H), 2.88-2.79 (m, 1H), 2.57-2.48 (m, 2H), 2.41(s, 3H), 2.25 (s, 3H), 2.04-1.95 (m, 2H), 1.95-1.78 (m, 4H). ESI m/z 338[M+H]⁺.

Preparation of1-(cyclopentylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine(Example 222)

A solution of Example 202 (175 mg, 0.56 mmol) and phosphorus (V)oxychloride (4 mL) was heated to 110° C. for 17 h. The reaction wasconcentrated in vacuo and saturated aq. NaHCO₃ (5 mL) and ethyl acetate(20 mL) were added. The ethyl acetate layer was separated, dried overNa₂SO₄, filtered and the filtrate was concentrated to a dark yellowsolid. The solid was dissolved in propionitrile (5 mL) and4-aminotetrahydropyran (283 mg, 28.0 mmol) was added. The stirredsolution was heated to 180° C. in a microwave reactor for 6 h. To thecooled mixture was added silica gel (10 g) and methanol (20 mL) and thesuspension was concentrated to a dry powder. This material was loadedonto silica gel (40 g) and eluted with 0-3% methanol in methylenechloride to give a yellow solid. The material was then purified byreverse phase HPLC on a Polaris column eluting with 10-90% CH₃CN in H₂Oand the clean fractions were frozen and lyophilized to give Example 222(70 mg, 31%) as a white solid: ¹H NMR (500 MHz, CD₃OD) δ 7.94 (d, J=1.5Hz, 1H), 7.50 (d, J=2.0 Hz, 1H), 4.17-4.05 (m, 1H), 4.05 (d, J=8.0 Hz,2H), 4.02-3.97 (m, 2H), 3.57 (t, J=11.75 Hz, 2H), 2.44-2.36 (m, 1H),2.41 (s, 3H), 2.25 (s, 3H), 2.08-2.00 (m, 2H), 1.78-1.64 (m, 6H),1.62-1.54 (m, 2H), 1.38-1.25 (m, 2H). ESI m/z 396 [M+H]⁺.

Preparation of1-(cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine(Example Compound 223)

Example Compound 223 was synthesized using a similar procedure as wasused, for Example Compound 222. Example Compound 223 collected as whitesolid (45 mg, 20% yield): ¹H NMR (500 MHz, CD₃OD) δ 7.93 (d, J=2.0 Hz,1H), 7.52 (d, J=2.0 Hz, 1H), 4.17-4.05 (m, 1H), 4.10 (d, J=7.5 Hz, 2H),4.03-3.97 (m, 2H), 3.56 (t, J=11.75 Hz, 2H), 2.86-2.78 (m, 1H), 2.41 (s,3H), 2.25 (s, 3H), 2.08-1.92 (m, 8H), 1.75-1.64 (m, 2H). ESI m/z 382[M+H]⁺.

Preparation of4-(1-benzyl-7-methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole(Example Compound 241)

Step 1: To a solution of 107 (136 mg, 0.627 mmol) in THF (6 mL) wasadded di-tert-butyl dicarbonate (137 mg, 0.627 mmol) and the reactionwas stirred at rt for 16 h. The reaction was then concentrated and theresidue was purified by chromatography (silica gel, 0-25% ethylacetate/hexanes) to afford an off-white solid which was dissolved inCH₂Cl₂ (3 mL), benzaldehyde in CH₂Cl₂ (2 mL) was added followed by AcOH(2 drops). The reaction was stirred at rt for 1 h and NaBH(OAc)₃ (283mg, 1.34 mmol) was added. The reaction was then stirred at rt for 16 h.The reaction was quenched with saturated NaHCO₃ and extracted withCH₂Cl₂ (2×50 mL). The combined organics were dried with Na₂SO₄, filteredand concentrated. The residue was purified by chromatography (silicagel, 0-30% ethyl acetate/hexanes) to afford 108 (97 mg, 38%) as anoff-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 8.43 (s, 1H), 7.32-7.26 (m,4H), 7.23-7.00 (m, 1H), 6.95 (s, 2H), 4.87 (t, J=6.9 Hz, 1H), 4.31 (d,J=6.9 Hz, 2H), 3.64 (s, 3H), 1.42 (s, 9H).

Step 2: To a solution of 108 (135 mg, 0.332 mmol) in CH₂Cl₂ (5 mL) at 0°C. was added TFA (0.51 mL, 6.63 mmol) and the reaction was warmed toroom temperature and stirred for 16 h. The reaction was thenconcentrated to afford 109 (114 mg, 90%): ESI m/z 385 [M+H]⁺.

Step 3: Using the procedure used in General Procedure B step 1 startingwith compound 109 (114 mg, 0.296 mmol) afforded Example Compound 241 (45mg, 38%) as an off white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.72 (d,J=8.4 Hz, 1H), 7.36-7.26 (m, 4H), 7.03-7.00 (m, 2H), 5.81 (s, 2H), 3.13(s, 3H), 2.27 (s, 3H), 2.09 (s, 3H); ESI m/z 402 [M+H]⁺.

Preparation of1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazole-2-carboximidamide(Example Compound 243) and1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazole-2-carboxamide(Example Compound 244)

Step 1: To a solution of 20 (3.00 g, 10.8 mmol) in 1,4-dioxane (60 mL)and water (6 mL) was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(2.90 g, 13.0 mmol), tetrakis(triphenylphosphine)palladium(0) (624 mg,0.54 mmol) and potassium carbonate (2.98 g, 21.6 mmol). The reactionmixture was purged with nitrogen and heated at 90° C. for 18 h. Themixture was cooled to room temperature, concentrated and purified bychromatography (silica gel, 0-20% ethyl acetate in hexanes) to afford110 (3.18 g, 99%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 7.38 (d,J=8.3 Hz, 2H), 7.34 (t, J=7.3 Hz, 2H), 7.28 (t, J=7.1 Hz, 1H), 6.78 (d,J=7.8 Hz, 1H), 6.55 (dd, J=1.8, 7.7 Hz, 1H), 6.43 (d, J=1.8 Hz, 1H),4.35 (s, 2H), 3.88 (s, 1H), 3.42 (s, 2H), 2.23 (s, 3H), 2.11 (s, 3H);ESI m/z 294 [M+H]⁺.

Step 1: To a solution of 110 (100 mg, 0.34 mmol) in acetic acid (2 mL)was added methyl 2,2,2-trichloroacetimidate (66 mg, 0.38 mmol) at roomtemperature. The reaction mixture was stirred at room temperature for 1h and then water was added. The precipitate formed was collected byfiltration, the filter cake was washed with water, and dried undervacuum at 40° C. to afford 111 (110 mg, 77%) as an off-white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 7.93 (dd, J=0.4, 8.4 Hz, 1H), 7.40-7.25 (m,4H), 7.19-7.11 (m, 3H), 5.96 (s, 2H), 2.21 (s, 3H), 2.03 (s, 3H); ESIm/z 422 [M+H]⁺.

Step 2: To a solution of 111 (100 mg, 0.238 mmol) in ethanol (1 mL) wasadded concentrated ammonium hydroxide (1 mL). The reaction mixture washeated at 120° C. for 1 h. The mixture was cooled to room temperatureand concentrated. The residue was purified by chromatography (silicagel, 0-100% ethyl acetate in hexanes then to 20% methanol in ethylacetate) followed by reverse phase HPLC on a Polaris Cig column elutingwith 10-90% CH₃CN in H₂O to afford Example Compound 243 (21 mg, 25%) andExample Compound 244 (29 mg, 35%) as an off-white solids. ExampleCompound 243: ¹H NMR (500 MHz, DMSO-d₆) δ 7.77 (d, J=8.3 Hz, 1H), 7.49(s, 1H), 7.36 (s, 1H), 7.33-7.19 (m, 6H), 6.58 (s, 2H), 6.27 (s, 2H),2.32 (s, 3H), 2.15 (s, 3H); ESI m/z 346 [M+H]⁺; Example Compound 244: ¹HNMR (500 MHz, DMSO-d₆) δ 8.38 (s, 1H), 7.92 (s, 1H), 7.82 (d, J=8.5 Hz,1H), 7.63 (d, J=1.0 Hz, 1H), 7.33-7.28 (m, 5H), 7.27-7.22 (m, 1H), 6.02(s, 2H), 2.35 (s, 3H), 2.18 (s, 3H); ESI m/z 347 [M+H]⁺.

Preparation of1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-3-yl)-1H-benzo[d]imidazol-2-amine(Example Compound 248)

Step 1: A solution of 81 (500 mg, 1.57 mmol) and phosphorus(V)oxychloride (2 mL) was heated to 100° C. for 17 h. The reaction wasconcentrated in vacuo and saturated aq. NaHCO₃ (5 mL) and ethyl acetate(20 mL) were added. The ethyl acetate layer was separated, dried overNa₂SO₄, filtered and concentrated. The residue was purified bychromatography (silica gel, 0-30% ethyl acetate in hexanes) to afford112 (415 mg, 78%) as a light brown oil: ESI m/z 338 [M+H]⁺.

Step 2: A mixture of 112 (20 mg, 0.06 mmol), pyridin-3-amine (28 mg,0.30 mmol) and p-TsOH.H₂O (22 mg, 0.12 mmol) in NMP was heated at 190°C. in a microwave reactor for 2 h. The mixture was concentrated, and theresidue was purified by chromatography (silica gel, 0-100% ethyl acetatein hexanes) to afford Example Compound 248 as an light brown oil: ESIm/z 396 [M+H]⁺.

Preparation of3-(1-benzyl-1H-benzo[d]imidazol-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one(Example Compound 249)

Step 1: A solution of 113 (1.20 g, 4.51 mmol) and hydrazine monohydrate(3.27 mL, 67.65 mmol) in EtOH (20 mL) was heated to reflux for 16 h. Themixture was cooled to rt, the precipitate was collected by filtration,the filter cake was dried to afford 114 (1.02 g, 85%) as an off-whitesolid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.74 (s, 1H), 8.54 (s, 1H), 8.07 (s,1H), 7.73-7.67 (m, 2H), 7.38-7.26 (m, 5H), 5.54 (s, 2H), 4.47 (s, 2H).

Step 2: A suspension of 114 (500 mg, 1.88 mmol) and ethylisocyanate (160mg, 2.26 mmol) in THF was stirred at rt for 5 h. The mixture wasfiltered, the filter cake was washed with ethyl acetate, and dried toafford 115 (610 mg, 96%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ10.09 (s, 1H), 8.57 (s, 1H), 8.14 (s, 1H), 7.81-7.79 (m, 2H), 7.72 (d,J=8.4 Hz, 1H), 7.38-7.28 (m, 5H), 6.47 (t, J=5.4 Hz, 1H), 5.55 (s, 2H),3.09-3.00 (m, 2H), 1.00 (t, J=7.2 Hz, 3H).

Step 3: A suspension of 115 (337 mg, 1.0 mmol) in 3 N NaOH (5 mL) washeated to reflux for 16 h. The mixture was adjusted to pH 8 by 2 N HCl,and then was extracted with CH₂Cl₂ (3×50 mL). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated. The residuewas triturated with EtOAc/CH₂Cl₂ to afford Example Compound 249 as anoff-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.85 (s, 1H), 8.59 (s,1H), 7.81-7.76 (m, 2H), 7.43 (dd, J=8.1, 1.5 Hz, 1H), 7.35-7.28 (m, 5H),5.58 (s, 2H), 3.63 (q, J=7.2, Hz 2H), 0.98 (t, J=7.2 Hz, 3H); ESI m/z320 [M+H]⁺.

TABLE 2 Example Compounds Purity Example General HPLC Compound ChemicalName Structure procedure Characterization (%) 1 9-benzyl-2-(3,5-dimethylisoxazol- 4-yl)-9H- purin-6-amine

A ¹H NMR (300 MHz, DMSO-d₆) δ 8.29 (s, 1H), 7.36-7.28 (m, 7H), 5.38 (s,2H), 2.73 (s, 3H), 2.51 (s, 3H); ESI m/z 321 [M + H]⁺. 96.6 23-benzyl-5-(3,5- dimethylisoxazol- 4-yl)-1H- imidazo[4,5-b]pyridin-2(3H)- one

No general procedure ¹H NMR (300 MHz, DMSO-d₆) δ 11.31 (s, 1H), 7.40 (d,J = 7.8 Hz, 1H), 7.34- 7.25 (m, 5 H), 7.15 (d, J = 7.8 Hz, 1H), 5.03 (s,2H), 2.47 (s, 3H), 2.28 (s, 3H); ESI m/z 321 [M + H]⁺. >99 31-benzyl-5-(3,5- dimethylisoxazol- 4-yl)-1H- imidazo[4,5-b]pyridin-2(3H)- one

No general procedure ¹H NMR (300 MHz, DMSO-d₆) δ 11.76 (s, 1H), 7.44 (d,J = 7.8 Hz, 1H), 7.36- 7.28 (m, 5H), 7.11 (d, J = 7.8 Hz, 1H), 5.05 (s,2H), 2.49 (s, 3H), 2.32 (s, 3H); ESI m/z 321 [M + H]⁺. >99 44-(3-benzyl-3H- imidazo[4,5- b]pyridin-6-yl)- 3,5- dimethylisoxazole

B ¹H NMR (300 MHz, CDCl₃) δ 8.62 (s, 1H), 8.36 (br s, 1H), 7.65 (s, 1H),7.45 (s, 5H), 5.96 (s, 2H), 2.34 (s, 3H), 2.17 (s, 3H); ESI m/z 305 [M +H]⁺. >99 5 4-(1-benzyl-1H- imidazo[4,5- b]pyridin-6-yl)- 3,5-dimethylisoxazole

B ¹H NMR (300 MHz, CDCl₃) δ 8.62 (s, 1H), 8.36 (br s, 1H), 7.65 (s, 1H),7.45 (s, 5H), 5.96 (s, 2H), 2.34 (s, 3H), 2.17 (s, 3H); ESI m/z 305 [M +H]⁺. >99 6 3-benzyl-5-(3,5- dimethylisoxazol- 4- yl)benzo[d]oxazol-2(3H)-one

No general procedure ¹H NMR (300 MHz, DMSO-d₆) δ 7.47- 7.42 (m, 3H),7.40- 7.34 (m, 2H), 7.34- 7.28 (m, 1H), 7.23 (d, J = 1.6 Hz, 1H), 7.12(dd, J = 8.2 Hz, 7.7 Hz, 1H), 5.07 (s, 2H), 2.33 (s, 3H), 2.15 (s, 3H);ESI m/z 321 [M + H]⁺ >99 7 1-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-1H-benzo[d]imidazol- 4-amine

C ¹H NMR (300 MHz, CDCl₃) δ 7.95 (s, 1H), 7.37-7.34 (m, 3H), 7.23-7.20(m, 2H), 6.46 (d, J = 1.2 Hz, 1H), 6.40 (d, J = 1.2 Hz, 1H), 5.34 (s,2H), 2.31 (s, 3H), 2.16 (s, 3H); ESI MS m/z 319 [M + H]⁺ >99 81-benzyl-5-(3,5- dimethylisoxazol- 4-yl)-1H- benzo[d]imidazol- 7-amine

C ¹H NMR (300 MHz, CDCl₃) δ 8.15 (s, 1H), 7.43-7.40 (m, 3H), 7.23 (d, J= 1.2 Hz, 1H), 7.20-7.17 (m, 2H), 6.39 (d, J = 1.2 Hz, 1H), 5.69 (s,2H), 2.40 (s, 3H), 2.27 (s, 3H); ESI MS m/z 319 [M + H]⁺ 95.2 9N,1-dibenzyl-6- (3,5- dimethylisoxazol- 4-yl)-1H- benzo[d]imidazol-4-amine

C ¹H NMR (300 MHz, DMSO-d₆) δ 8.27 (s, 1H), 7.40-7.18 (m, 10H), 6.62 (d,J = 1.2 Hz, 1H), 6.57 (t, J = 6.0 Hz, 1H), 5.97 (d, J = 1.2 Hz, 1H),5.41 (s, 2H), 4.48 (d, J = 6.0 Hz, 2H), 2.12 (s, 3H), 1.94 (s, 3H); ESIMS m/z 409 [M + H]⁺. >99 10 1-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-1H-imidazo[4,5- b]pyridin-2(3H)- one

No general procedure ¹H NMR (300 MHz, DMSO-d₆) δ 11.81 (s, 1H), 7.90 (d,J = 2.1 Hz, 1H), 7.44- 7.25 (m, 6H), 5.05 (s, 2H), 2.34 (s, 3H), 2.16(s, 3H); MM m/z 321 [M + H]⁺. >99 11 1-benzyl-7-(3,5- dimethylisoxazol-4- yl)quinoxalin- 2(1H)-one

No general procedure ¹H NMR (300 MHz, CDCl₃) δ 8.43 (s, 1H), 7.94 (d, J= 8.2 Hz, 1H), 7.35-7.32 (m, 2H), 7.29-7.27 (m, 1H), 7.21-7.18 (m, 3H),7.04 (s, 1H), 5.51 (s, 2H), 2.16 (s, 3H), 2.02 (s, 3H); ESI m/z 332 [M +H]⁺. >99 12 1-benzyl-7-(3,5- dimethylisoxazol- 4-yl)-3,4-dihydroquinazolin- 2(1H)-one

No general procedure ¹H NMR (500 MHz, DMSO-d₆) δ 7.34 7.21 (m, 7H), 6.90(dd, J = 7.5, 1.0 Hz, 1H), 6.58 (d, J = 1.0 Hz, 1H), 5.09 (s, 2H), 4.43(s, 2H), 2.06 (s, 3H), 1.89 (s, 3H); MM m/z 334 [M + H]⁺. >99 134-(1-benzyl-2- methyl-1H- imidazo[4,5- b]pyridin-6-yl)- 3,5-dimethylisoxazole

D ¹H NMR (500 MHz, CD₃OD) δ 8.32 (d, J = 1.0 Hz, 1H), 7.78 (d, J = 1.0Hz, 1H), 7.36-7.29 (m, 3H), 7.20-7.17 (m, 2H), 5.56 (s, 2H), 2.69 (s,3H), 2.36 (s, 3H), 2.18 (s, 3H); ESI m/z >99 319 [M + H]⁺. 14 4-(1-(cyclopropylmethyl)- 2-methyl- 4-nitro-1H- benzo[d]imidazol- 6-yl)-3,5-dimethylisoxazole

F ¹H NMR (500 MHz, CD₃OD) δ 8.03 (d, J = 1.5 Hz, 1H), 7.93 (d, J = 1.5Hz, 1H), 4.27 (d, J = 7.0 Hz, 2H), 2.75 (s, 3H), 2.46 (s, 3H), 2.30 (s,3H), 1.38-1.28 (m, 1H), 0.65-0.60 (m, 2H), 0.51-0.46 (m, 2H). ESI m/z327 97.3 [M + H]⁺ 15 1-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-4-nitro-1H- benzo[d]imidazol- 2(3H)-one

G ¹H NMR (300 MHz, DMSO-d₆) δ 12.11 (s, 1H), 7.72 (d, J = 1.5 Hz, 1H),7.50 (d, J = 1.5 Hz, 1H), 7.42- 7.28 (m, 5H), 5.13 (s, 2H), 2.35 (s,3H), 2.15 (s, 3H); ESI m/z 365 [M + H]⁺. 98.5 16 4-amino-1-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-1H- benzo[d]imidazol- 2(3H)-one

G ¹H NMR (500 MHz, DMSO-d₆) δ 10.44 (s, 1H), 7.36-7.25 (m, 5H), 6.28 (s,2H), 5.04 (s, 2H), 4.95 (s, 2H), 2.28 (s, 3H), 2.10 (s, 3H); ESI m/z 335[M + H]⁺. 98.6 17 1-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-2- ethoxy-1H-benzo[d]imidazol- 4-amine

No general procedure ¹H NMR (300 MHz, CDCl₃) δ 7.35-7.20 (m, 5H), 6.33(d, J = 1.5 Hz, 1H), 6.30 (d, J = 1.5 Hz, 1H), 5.13 (s, 2H), 4.68 (q, J= 6.9 Hz, 2H), 4.30 (br. s, 2H), 2.30 (s, 3H), 2.16 (s, 3H), 1.49 (t, J= 7.2 Hz, 3H); ESI m/z 363 [M + H]⁺. 99 18 1-benzyl-6-(3,5-dimethylisoxazol- 4-yl)-N-ethyl- 4-nitro-1H- benzo[d]imidazol- 2-amine

I ¹H NMR (300 MHz, CDCl₃) δ 7.84 (d, J = 1.5 Hz, 1H), 7.42- 7.35 (m,3H), 7.16- 7.13 (m, 2H), 7.03 (d, J = 1.5 Hz, 1H), 5.15 (s, 2H), 4.29(t, J = 5.4 Hz, 1H), 3.78- 3.69 (m, 2H), 2.36 (s, 3H), 2.21 (s, 3H),1.27 (t, J = 7.5 Hz, 3H); ESI m/z 392 99 [M + H]⁺. 19 1-benzyl-6-(3,5-dimethylisoxazol- 4-yl)-N2- ethyl-1H- benzo[d]imidazole- 2,4-diamine

I ¹H NMR (300 MHz, DMSO-d₆) δ 7.34- 7.20 (m, 5H), 6.62 (t, J = 5.4 Hz,1H), 6.30 (d, J = 1.5 Hz, 1H), 6.21 (d, J = 1.5 Hz, 1H), 5.19 (s, 2H),4.83 (s, 2H), 3.47- 3.38 (m, 2H), 2.28 (s, 3H), 2.11 (s, 3H), 1.22 (t, J= 7.2 Hz, 3H); ESI m/z 362 96.8 [M + H]⁺. 20 methyl 1- benzyl-6-(3,5-dimethylisoxazol- 4-yl)-2-oxo- 2,3-dihydro-1H- benzo[d]imidazole- 4-carboxylate

J ¹H NMR (500 MHz, CD₃OD) δ 7.54 (d, J = 1.5 Hz, 1H), 7.37- 7.24 (m,5H), 7.07 (d, J = 1.5 Hz, 1H), 5.14 (s, 2H), 3.97 (s, 3H), 2.27 (s, 3H),2.09 (s, 3H); ESI m/z 378 [M + H]⁺. >99 21 1-benzyl-6-(3,5-dimethylisoxazol- 4-yl)-2-oxo- 2,3-dihydro-1H- benzo[d]imidazole- 4-carboxamide

J ¹H NMR (500 MHz, CD₃OD) δ 7.41 (d, J = 1.3 Hz, 1H), 7.37- 7.24 (m,5H), 7.00 (d, J = 1.4 Hz, 1H), 5.13 (s, 2H), 2.28 (s, 3H), 2.11 (s, 3H);ESI m/z 363 [M + H]⁺. 98.3 22 4- (aminomethyl)- 1-benzyl-6-(3,5-dimethylisoxazol- 4-yl)-1H- benzo[d]imidazol- 2(3H)-one

J ¹H NMR (500 MHz, CD₃OD) δ 7.37-7.23 (m, 5H), 6.99 (d, J = 1.4 Hz, 1H),6.77 (d, J = 1.4 Hz, 1H), 5.10 (s, 2H), 3.93 (s, 2H), 2.27 (s, 3H), 2.10(s, 3H); ESI m/z 349 [M + H]⁺. 93.9 23 5-(3,5- dimethylisoxazol-4-yl)-N- phenyl-1H- pyrrolo[3,2- b]pyridin-3- amine

M ¹H NMR (300 MHz, DMSO-d₆) 11.1 (d, J = 1.8 Hz, 1H), 7.82 (d, J = 8.4Hz, 1H), 7.61 (d, J = 2.7 Hz, 1H), 7.43 (s, 1H), 7.25 (d, J = 8.4 Hz,1H), 7.09 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 7.2 Hz, 1H), 6.85 (d, >99 J= 7.5 Hz, 2H), 6.60 (t, J = 7.2 Hz, 1H), 2.48 (s, 3H), 2.29 (s, 3H); ESIMS m/z 305 [M + H]⁺. 24 6-(3,5- dimethylisoxazol- 4-yl)-1-(4-fluorobenzyl)-3- methyl-1H- pyrazolo[4,3- b]pyridine 4- oxide

N ¹H NMR (300 MHz, DMSO-d₆) δ 8.21 (d, J = 0.9 Hz, 1H), 7.83 (d, J = 0.9Hz, 1H), 7.40-7.35 (m, 2H), 7.20-7.14 (m, 2H), 5.59 (s, 2H), 2.69 (s,3H), 2.45 (s, 3H), 2.27 (s, 3H); ESI MS m/z 353 [M + H]⁺. >99 25 6-(3,5-dimethylisoxazol- 4-yl)-1-(4- fluorobenzyl)-3- methyl-1H- pyrazolo[4,3-b]pyridin-5(4H)- one

N ¹H NMR (300 MHz, DMSO-d₆) δ 12.0 (s, 1H), 8.07 (s, 1H), 7.36-7.31 (m,2H), 7.19-7.13 (m, 2H), 5.45 (s, 2H), 2.30 (s, 6H), 2.14 (s, 3H); ESI MSm/z 353 [M + H]⁺. 96.2 26 4-(3-benzyl-3H- imidazo[4,5- b]pyridin-5-yl)-3,5- dimethylisoxazole

No general procedure ¹H NMR (300 MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.17 (d,J = 8.1 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.36- 7.27 (m, 5H), 5.52 (s,2H), 2.54 (s, 3H), 2.34 (s, 3H); ESI m/z 305 [M + H]⁺. 98 27 6-(3,5-dimethylisoxazol- 4-yl)-1-(4- fluorobenzyl)- 1H- benzo[d]imidazol-4-amine

C ¹H NMR (300 MHz, DMSO-d₆) δ 8.23 (s, 1H), 7.42 (dd, J = 8.0, 6.0 Hz,2H), 7.17 (dd, J = 9.0, 9.0 Hz, 2H), 6.62 (s, 1H), 6.32 (s, 1H), 5.40(s, 4H), 2.33 (s, 3H), 2.16 (s, 3H); ESI m/z 337 [M + H]⁺. >99 286-(3,5- dimethylisoxazol- 4-yl)-1-(4- fluorobenzyl)- N-methyl-1H-benzo[d]imidazol- 4-amine

No general procedure ¹H NMR (500 MHz, DMSO-d₆) δ 8.22 (s, 1H), 7.43 (dd,J = 8.8, 5.5 Hz, 2H), 7.16 (dd, J = 8.8, 5.5 Hz, 2H), 6.65 (d, J = 1.0Hz, 1H), 5.85 (q, J = 5.0 Hz, 1H), 5.41 (s, 2H), 2.83 (d, J = 5.5 Hz,3H), 2.35 (s, 3H), 2.17 (s, 3H); ESI m/z 351 [M + H]⁺ >99 29 6-(3,5-dimethylisoxazol- 4-yl)-1-(4- fluorobenzyl)- N,N-dimethyl- 1H-benzo[d]imidazol- 4-amine

No general procedure ¹H NMR (500 MHz, DMSO-d₆) δ 8.28 (s, 1H), 7.41 (dd,J = 8.5, 5.5 Hz, 2H), 7.17 (dd, J = 9.0, 9.0 Hz, 2H), 6.85 (d, J = 1.0Hz, 1H), 6.25 (d, J = 1.0 Hz, 1H), 5.43 (s, 2H), 3.18 (s, 6H), 2.35 (s,3H), 2.18 (s, 3H); ESI m/z 365 [M + H]⁺. 98.1 30 3,5-dimethyl-4- (1-(1-phenylethyl)- 1H-imidazo[4,5- b]pyridin-6- yl)isoxazole

No general procedure ¹H NMR (500 MHz, CD₃OD) δ 8.76 (s, 1H), 8.36 (d, J= 2.0 Hz, 1H), 7.65 (d, J = 2.5 Hz, 1H), 7.40- 7.30 (m, 5H), 4.44 (q, J= 7.0 Hz, 1H), 2.29 (s, 3H), 2.10 (s, 3H), 2.06 (d, J = 7.0 98.6 Hz,3H). ESI m/z 319 [M + H]⁺. 31 4-(1-benzyl-1H- imidazo[4,5-c]pyridin-6-yl)- 3,5- dimethylisoxazole

No general procedure ¹H NMR (500 MHz, CD₃OD) δ 9.00 (d, J = 1.0 Hz, 1H),8.05 (s, 1H), 7.48 (d, J = 1.0 Hz, 1H), 7.40- 7.30 (m, 5H), 5.58 (s,2H), 2.40 (s, 3H), 2.25 (s, 3H); ESI m/z 305 [M + H]⁺. 98.6 321-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-1H- imidazo[4,5- c]pyridine 5-oxide

No general procedure ¹H NMR (500 MHz, CD₃OD) δ 8.92 (s, 1H), 8.61 (s,1H), 7.67 (s, 1H), 7.45- 7.25 (m, 5H), 6.57 (s, 2H), 2.28 (s, 3H), 2.17(s, 3H); ESI m/z 321 [M + H]⁺. 98.7 33 1-benzyl-6-(3,5-dimethylisoxazol- 4-yl)-1H- imidazo[4,5- c]pyridin-4- amine

No general procedure ¹H NMR (500 MHz, CD₃OD) δ 8.21 (s, 1H), 7.42-7.25(m, 5H), 6.70 (s, 1H), 5.46 (s, 2H), 2.39 (s, 3H), 2.24 (s, 3H); ESI m/z320 [M + H]⁺. 96.9 34 4-(1-benzyl-3- bromo-1H- pyrrolo[3,2-b]pyridin-6-yl)- 3,5- dimethylisoxazole

No general procedure ¹H NMR (500 MHz, CD₃OD) δ 8.33 (d, J = 1.5 Hz, 1H),7.86 (s, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.34- 7.24 (m, 5H), 5.48 (s,2H), 2.35 (s, 3H), 2.17 (s, 3H); ESI MS m/z 382 [M + H]⁺. >99 351-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-1H- pyrrolo[3,2- b]pyridine-3-carbaldehyde

No general procedure ¹H NMR (300 MHz, DMSO-d₆) δ 10.2 (s, 1H), 8.73 (s,1H), 8.53 (d, J = 1.8 Hz, 1H), 8.11 (d, J = 1.8 Hz, 1H), 7.44-7.30 (m,5H), 5.59 (s, 2H), 2.40 (s, 3H), 2.21 (s, 3H); ESI MS m/z 332 [M +H]⁺ >99 36 1-(1-benzyl-6- (3,5- dimethylisoxazol- 4-yl)-1H- pyrrolo[3,2-b]pyridin-3- yl)ethanone

No general procedure ¹H NMR (300 MHz, CDCl₃) δ 8.59 (d, J = 1.5 Hz, 1H),8.22 (s, 1H), 7.45 (d, J = 1.8 Hz, 1H), 7.40-7.36 (m, 3H), 7.21-7.18 (m,2H), 5.40 (s, 2H), 2.89 (s, 3H), 2.34 (s, 3H), 2.17 (s, 3H); ESI MS m/z346 [M + H]⁺. >99 37 1-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-1H-pyrrolo[3,2- b]pyridin-5-yl formate

No general procedure ¹H NMR (300 MHz, CDCl₃) δ 9.90 (s, 1H), 7.62 (s,1H), 7.43-7.41 (m, 3H), 7.28 (s, 1H), 7.22- 7.18 (m, 3H), 5.31 (s, 2H),2.22 (s, 3H), 2.10 (s, 3H); ESI MS m/z 348 [M + H]⁺. >99 38 4-((6-(3,5-dimethylisoxazol- 4-yl)-2- methyl-1H- imidazo[4,5- b]pyridin-1-yl)methyl) benzamide

No general procedure ¹H NMR (300 MHz, DMSO-d₆) δ 8.35 (d, J = 1.8 Hz,1H), 7.99 (d, J = 2.1 Hz, 1H), 7.94 (br. s, 1H), 7.83 (d, J = 8.4 Hz,2H), 7.37 (br. s, 1H), 7.27 (d, J = 8.4 Hz, 2H), 5.61 (s, 2H), 2.60 (s,3H), 2.39 (s, 3H), 2.21 (s, 3H); ESI m/z >99 362 [M + H]⁺. 394-(1-benzyl-3- nitro-1H- pyrrolo[3,2- b]pyridin-6-yl)- 3,5-dimethylisoxazole

No general procedure ¹H NMR (300 MHz, CDCl₃) δ 8.74 (s, 1H), 8.47 (s,1H), 7.56 (s, 1H), 7.45-7.42 (m, 3H), 7.27-7.26 (m, 2H), 5.47 (s, 2H),2.35 (s, 3H), 2.17 (s, 3H); ESI MS m/z 349 [M + H]⁺. >99 403,5-dimethyl-4- (3-(4- (trifluoromethyl) benzyl)-3H- imidazo[4,5-b]pyridin-6- yl)isoxazole

B ¹H NMR (300 MHz, CDCl₃) δ 8.33 (d, J = 2.1 Hz, 1H), 8.15 (s, 1H), 8.00(d, J = 2.1 Hz, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H),5.58 (s, 2H), 2.44 (s, 3H), 2.30 (s, 3H); MM m/z 373 [M + H]⁺ 98.3 413,5-dimethyl-4- (1-(4- (trifluoromethyl) benzyl)-1H- imidazo[4,5-b]pyridin-6- yl)isoxazole

B ¹H NMR (300 MHz, CDCl₃) δ 8.49 (d, J = 2.1 Hz, 1H), 8.29 (s, 1H), 7.66(d, J = 8.1 Hz, 2H), 7.34-7.30 (m, 3H), 5.50 (s, 2H), 2.33 (s, 3H), 2.16(s, 3H); MM m/z 373 [M + H]⁺ 98.9 42 4-(3-(4- chlorobenzyl)-3H-imidazo[4,5- b]pyridin-6-yl)- 3,5- dimethylisoxazole

B ¹H NMR (300 MHz, CDCl₃) δ 8.32 (d, J = 2.1 Hz, 1H), 8.11 (s, 1H), 7.98(d, J = 2.l1 Hz, 1H), 7.37-7.27 (m, 4H), 5.48 (s, 2H), 2.44 (s, 3H),2.29 (s, 3H); MM m/z 339 [M + H]⁺. >99 43 4-(1-(4- chlorobenzyl)-1H-imidazo[4,5- b]pyridin-6-yl)- 3,5- dimethylisoxazole

B ¹H NMR (300 MHz, CDCl₃) δ 8.47 (d, J = 2.1 Hz, 1H), 8.25 (s, 1H), 7.37(d, J = 8.7 Hz, 2H), 7.32 (d, J = 2.1 Hz, 1H), 7.16 (d, J = 8.7 Hz, 2H),5.39 (s, 2H), 2.35 (s, 3H), 2.18 (s, 3H); MM m/z 339 [M + H]⁺ >99 444-(3-(4- fluorobenzyl)- 3H-imidazo[4,5- b]pyridin-6-yl)- 3,5-dimethylisoxazole

B ¹H NMR (300 MHz, CDCl3) δ 8.33 (d, J = 2.1 Hz, 1H), 8.10 (s, 1H), 7.98(d, J = 2.1 Hz, 1H), 7.38-7.33 (m, 2H), 7.09-7.03 (m, 2H), 5.48 (s, 2H),2.44 (s, 3H), 2.30 (s, 3H); MM m/z 323 [M + H]+ >99 45 4-(1-(4-fluorobenzyl)- 1H-imidazo[4,5- b]pyridin-6-yl)- 3,5- dimethylisoxazole

B ¹H NMR (300 MHz, CDCl₃) δ 8.47 (d, J = 2.1 Hz, 1H), 8.25 (s, 1H), 7.34(d, J = 2.1 Hz, 1H), 7.24-7.19 (m, 2H), 7.09 (t, J = 8.7 Hz, 2H), 5.38(s, 2H), 2.35 (s, 3H), 2.18 (s, 3H); MM 98.4 m/z 323 [M + H]⁺ 463,5-dimethyl-4- (3-(pyridin-2- ylmethyl)-3H- imidazo[4,5- b]pyridin-6-yl)isoxazole

B ¹H NMR (300 MHz, CDCl₃) δ 8.62-8.59 (m, 1H), 8.33 (s, 1H), 8.31 (d, J= 2.1 Hz, 1H), 7.98 (d, J = 2.1 Hz, 1H), 7.71-7.65 (m, 1H), 7.33-7.23(m, 2H), 5.63 (s, 2H), 2.43 (s, 3H), 2.29 (s, 3H); MM m/z 306 [M + H]⁺95.5 47 3,5-dimethyl-4- (1-(pyridin-2- ylmethyl)-1H- imidazo[4,5-b]pyridin-6- yl)isoxazole

B ¹H NMR (300 MHz, CDCl₃) δ 8.62-8.59 (m, 1H), 8.46 (d, J = 2.1 Hz, 1H),8.34 (s, 1H), 7.72-7.66 (m, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.31-7.27 (m,1H), 7.13 (d, J = 7.8 Hz, 1H), 5.51 (s, 2H), 2.38 (s, 3H), 98.3 2.22 (s,3H); MM m/z 306 [M + H]⁺ 48 4-(1-(4- fluorobenzyl)- 1H-pyrrolo[3,2-b]pyridin-6-yl)- 3,5- dimethylisoxazole

A: using 6- bromo-1H- pyrrolo[3,2- b]pyridine as starting material ¹HNMR (300 MHz, CD₃OD) δ 8.26 (d, J = 1.8 Hz, 1H), 7.78 (dd, J = 0.9, 1.8Hz, 1H), 7.75 (d, J = 3.3 Hz, 1H), 7.29-7.24 (m, 2H), 7.08-7.02 (m, 2H),6.70 (dd, J = 0.6, 3.3 Hz, 1H), 97.6 5.47 (s, 2H), 2.36 (s, 3H), 2.19(s, 3H); ESI MS m/z 322 [M + H]⁺. 49 4-(1-(4- fluorobenzyl)-1H-pyrrolo[2,3- b]pyridin-6-yl)- 3,5- dimethylisoxazole

A: using 6- bromo-1H- pyrrolo[2,3- b]pyridine as starting material ¹HNMR (300 MHz, CD₃OD) δ 8.04 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 3.6 Hz,1H), 7.26-7.21 (m, 3H), 7.04-6.98 (m, 2H), 6.55 (d, J = 3.6 Hz, 1H),5.50 (s, 2H), 2.53 (s, 3H), 2.37 (s, >99 3H); ESI MS m/z 322 [M + H]⁺.50 4-(5-(4- fluorobenzyl)- 5H-pyrrolo[2,3- b]pyrazin-3-yl)- 3,5-dimethylisoxazole

A: using 3- bromo-5H- pyrrolo[2,3- b]pyrazine as starting material ¹HNMR (300 MHz, CD₃OD) δ 8.54 (s, 1H), 7.91 (d, J = 3.6 Hz, 1H), 7.35-7.30(m, 2H), 7.08-7.02 (m, 2H), 6.72 (d, J = 3.6 Hz, 1H), 5.52 (s, 2H), 2.60(s, 3H), 2.42 (s, 3H); ESI MS >99 m/z 323 [M + H]⁺. 51 4-(1-(4-fluorobenzyl)- 1H- pyrazolo[4,3- b]pyridin-6-yl)- 3,5- dimethylisoxazole

A: using 6- bromo-1H- pyrazolo[4, 3- b]pyridine as starting material ¹HNMR (300 MHz, CD₃OD) δ 8.50 (d, J = 1.8 Hz, 1H), 8.28 (d, J = 0.9 Hz,1H), 8.05 (dd, J = 1.8, 1.2 Hz, 1H), 7.36-7.31 (m, 2H), 7.08-7.02 (m,2H), 5.70 (s, 2H), 2.42 (s, 3H), 2.25 (s, 98.5 3H); ESI MS m/z 323 [M +H]⁺. 52 6-(3,5- dimethylisoxazol- 4-yl)-1-(4- fluorobenzyl)-1H-pyrrolo[2,3- b]pyridin-4- amine

A: using 6- bromo-1H- pyrrolo[2,3- b]pyridin- 4-amine as startingmaterial ¹H NMR (300 MHz, DMSO-d₆) d 7.29- 7.24 (m, 3H), 7.15- 7.09 (m,2H), 6.55 (d, J = 3.6 Hz, 1H), 6.35 (s, 1H), 6.33 (s, 2H), 5.33 (s, 2H),2.49 (s, 3H), 2.32 (s, 3H); ESI MS m/z 337 [M + H]⁺. >99 53 4-(1-(4-fluorobenzyl)-3- methyl-1H- pyrazolo[4,3- b]pyridin-6-yl)- 3,5-dimethylisoxazole

A: using 6- bromo-3- methyl-1H- pyrazolo[4, 3- b]pyridine as startingmaterial ¹H NMR (300 MHz, CD₃OD) δ 8.45 (d, J = 1.8 Hz, 1H), 7.98 (d, J= 1.8 Hz, 1H), 7.34-7.29 (m, 2H), 7.08-7.02 (m, 2H), 5.61 (s, 2H), 2.65(s, 3H), 2.42 (s, 3H), 2.25 (s, 3H); ESI MS m/z 337 96.7 [M + H]⁺. 541-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-1H- indazol-4-amine

B: using 6- bromo-1H- indazol-4- amine as starting material ¹H NMR (300MHz, DMSO-d₆) δ 8.13 (d, J = 0.6 Hz, 1H), 7.32- 7.23 (m, 5H), 6.70 (s,1H), 6.11 (d, J = 1.2 Hz, 1H), 5.97 (s, 2H), 5.53 (s, 2H), 2.37 (s, 3H),2.19 (s, 3H); ESI MS m/z 319 [M + H]⁺. >99 55 1-benzyl-6-(3,5-dimethylisoxazol- 4-yl)-2- methyl-1H- benzo[d]imidazol- 4-amine

K ¹H NMR (500 MHz, CDCl₃) δ 7.34-7.28 (m, 3H), 7.09-7.08 (m, 2H), 6.42(d, J = 1.5 Hz, 1H), 6.36 (d, J = 1.5 Hz, 1H), 5.28 (s, 2H), 4.42 (br.s, 2H), 2.60 (s, 3H), 2.31 (s, 3H), 2.17 (s, 3H); ESI m/z 333 [M + H]⁺.99 56 1-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-1H- pyrrolo[3,2-b]pyridin-5(4H)- one

N ¹H NMR (500 MHz, DMSO-d₆) δ 8.15 (d, J = 1.5 Hz, 1H), 7.83 (d, J = 3.5Hz, 1H), 7.64 (s, 1H), 7.34- 7.32 (m, 5H), 6.75 (d, J = 2.5 Hz, 1H),5.50 (s, 2H), 2.39 (s, 3H), 2.20 (s, 3H); ESI MS m/z 320 [M + H]⁺. >9957 3-((5-(3,5- dimethylisoxazol- 4-yl)-1H- pyrrolo[3,2- b]pyridin-3-yl)amino) benzonitrile

M ¹H NMR (300 MHz, DMSO-d₆) δ 11.5 (s, 1H), 7.98 (s, 2H), 7.78 (s, 1H),7.36- 7.25 (m, 2H), 7.11- 7.07 (m, 1H), 7.01- 6.99 (m, 2H), 2.46 (s,3H), 2.26 (s, 3H); ESI MS m/z 330 >99 [M + H]⁺. 58 4-(1-(4-fluorobenzyl)-2- methyl-1H- imidazo[4,5- b]pyridin-6-yl)- 3,5-dimethylisoxazole

D ¹H NMR (300 MHz, DMSO-d₆) δ 8.34 (d, J = 1.8 Hz, 1H), 7.99 (d, J = 2.1Hz, 1H), 7.32-7.26 (m, 2H), 7.22-7.15 (m, 2H), 5.53 (s, 2H), 2.61 (s,3H), 2.40 (s, 3H), 2.22 (s, 3H); ESI m/z 98.9 337 [M + H]⁺. 584-(1-benzyl-2- ethoxy-1H- imidazo[4,5- b]pyridin-6-yl)- 3,5-dimethylisoxazole

No general procedure ¹H NMR (300 MHz, DMSO-d₆) δ 7.75 (d, J = 1.2 Hz,1H), 7.38- 7.22 (m, 5H), 7.18 (d, J = 1.5 Hz, 1H), 4.99 (s, 2H), 4.34(q, J = 7.2 Hz, 2H), 2.37 (s, 3H), 2.18 (s, 3H), 1.42 (t, J = 7.2Hz, >99 3H); ESI m/z 349 [M + H]⁺. 60 4-((6-(3,5- dimethylisoxazol-4-yl)-2- methyl-1H- imidazo[4,5- b]pyridin-1- yl)methyl)-3,5-dimethylisoxazole

D ¹H NMR (300 MHz, DMSO-d₆) δ 8.35 (d, J = 1.8 Hz, 1H), 7.93 (d, J = 2.1Hz, 1H), 5.37 (s, 2H), 2.56 (s, 3H), 2.41 (s, 3H), 2.33 (s, 3H), 2.23(s, 3H), 1.91 (s, 3H); ESI m/z 338 [M + H]⁺. >99 61 4-(1-(2,4-dichlorobenzyl)- 2-methyl-1H- imidazo[4,5- b]pyridin-6-yl)- 3,5-dimethylisoxazole

D ¹H NMR (300 MHz, DMSO-d₆) δ 8.36 (d, J = 2.1 Hz, 1H), 7.88 (d, J = 1.8Hz, 1H), 7.74 (d, J = 2.1 Hz, 1H), 7.38 (dd, J = 8.4, 2.1 Hz, 1H), 6.77(d, J = 8.4 Hz, 1H), 5.61 (s, 2H), 2.54 (s, 3H), 2.38 (s, >99 3H), 2.19(s, 3H); ESI m/z 387 [M + H]⁺. 62 4-(1-(4- methoxybenzyl)- 2-methyl-1H-imidazo[4,5- b]pyridin-6-yl)- 3,5- dimethylisoxazole

D ¹H NMR (300 MHz, DMSO-d₆) δ 8.33 (d, J = 1.8 Hz, 1H), 7.98 (d, J = 2.1Hz, 1H), 7.21 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 5.46 (s,2H), 3.71 (s, 3H), 2.61 (s, 3H), 2.40 (s, 3H), >99 2.22 (s, 3H); ESI m/z349 [M + H]⁺. 63 4-(1- (cyclopropylmethyl)- 2-methyl- 1H-imidazo[4,5-b]pyridin-6-yl)- 3,5- dimethylisoxazole

D ¹H NMR (300 MHz, DMSO-d₆) δ 8.31 (d, J = 2.1 Hz, 1H), 8.05 (d, J = 2.1Hz, 1H), 4.17 (d, J = 7.2 Hz, 2H), 2.65 (s, 3H), 2.44 (s, 3H), 2.26 (s,3H), 1.31-1.18 (m, 97.4 1H), 0.54-0.48 (m, 2H), 0.46-0.41 (m, 2H); ESIm/z 283 [M + H]⁺. 64 N-(1-benzyl-6- (3,5- dimethylisoxazol- 4-yl)-2-methyl-1H- benzo[d]imidazol- 4- yl)acetamide

K ¹H NMR (300 MHz, CDCl₃) δ 8.59 (br. s, 1H), 8.20 (s, 1H), 7.38-7.31(m, 3H), 7.09-7.06 (m, 2H), 6.76 (d, J = 1.2 Hz, 1H), 5.34 (s, 2H), 2.65(s, 3H), 2.35 (s, 3H), 2.31 (s, 3H), 2.21 (s, 3H); ESI m/z 375 [M + H]⁺.97.4 65 N-(1-benzyl-6- (3,5- dimethylisoxazol- 4-yl)-2- methyl-1H-benzo[d]imidazol- 4-yl) ethanesulfonamide

K ¹H NMR (300 MHz, CDCl₃) δ 7.71 (br. s, 1H), 7.39-7.30 (m, 4H),7.12-7.09 (m, 2H), 6.79 (d, J = 1.2 Hz, 1H), 5.33 (s, 2H), 3.21 (q, J =7.5 Hz, 2H), 2.64 (s, 3H), 2.35 (s, 3H), 2.20 (s, 3H), 1.42 (t, J = 7.5Hz, 3H); APCI m/z 425 [M + H]⁺. 95.7 66 4-(1-benzyl-4- methoxy-2-methyl-1H- benzo[d]imidazol- 6-yl)-3,5- dimethylisoxazole

No general procedure ¹H NMR (300 MHz, CDCl₃) δ 7.35-7.30 (m, 3H),7.09-7.06 (m, 2H), 6.64 (d, J = 1.2 Hz, 1H), 6.53 (s, 1H), 5.32 (s, 2H),4.03 (s, 3H), 2.66 (s, 3H), 2.33 (s, 3H), 2.19 (s, 3H); ESI m/z 348 [M +H]⁺. 93.7 67 7-amino-3- benzyl-5-(3,5- dimethylisoxazol-4-yl)benzo[d]oxazol- 2(3H)-one

G ¹H NMR (300 MHz, DMSO-d₆) δ 7.43- 7.30 (m, 5H), 6.40 (d, J = 1.5 Hz,1H), 6.39 (d, J = 1.5 Hz, 1H), 5.58 (s, 2H), 4.99 (s, 2H), 2.31 (s, 3H),2.13 (s, 3H); ESI m/z 336 [M + H]⁺. 97.6 68 3,5-dimethyl-4- (2-methyl-1-(pyridin-3- ylmethyl)-1H- imidazo[4,5- b]pyridin-6- yl)isoxazole

D ¹H NMR (300 MHz, DMSO-d₆) δ 8.58 (d, J = 1.8 Hz, 1H), 8.51 (dd, J =4.7, 1.8 Hz, 1H), 8.35 (d, J = 2.1 Hz, 1H), 8.03 (d, J = 2.1 Hz, 1H),7.60 (dt, J = 8.1, 1.8 Hz, 1H), 7.37 (ddd, J = 7.8, 96.5 4.8, 0.6 Hz,1H), 5.60 (s, 2H), 2.64 (s, 3H), 2.40 (s, 3H), 2.21 (s, 3H); ESI m/z 320[M + H]⁺ 69 3,5-dimethyl-4- (2-methyl-1- (thiophen-2- ylmethyl)-1H-imidazo[4,5- b]pyridin-6- yl)isoxazole

D ¹H NMR (300 MHz, DMSO-d₆) δ 8.34 (d, (d, J = 2.1 Hz, 1H), 7.48 (dd, J= 5.1, 1.2 Hz, 1H), 7.25 (dd, J = 3.1, 1.2 Hz, 1H), 7.00 (dd, J = 5.1,3.3 Hz, 1H), 5.75 (s, 2H), >99 2.67 (s, 3H), 2.44 (s, 3H), 2.26 (s, 3H);ESI m/z 325 [M + H]⁺. 70 4-((6-(3,5- dimethylisoxazol- 4-yl)-2-methyl-1H- imidazo[4,5- b]pyridin-1- yl)methyl) benzonitrile

D ¹H NMR (300 MHz, DMSO-d₆) δ 8.36 (d, J = 2.1 Hz, 1H), 7.98 (s, J = 2.1Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 5.67 (s,2H), 2.57 (s, 3H), 2.39 (s, 3H), 2.21 (s, 3H); ESI 98.3 m/z 344 [M +H]⁺. 71 4-(1-benzyl-1H- pyrrolo[3,2- b]pyridin-6-yl)- 3,5-dimethylisoxazole

B: using 6- bromo-1H- pyrrolo[3,2- b]pyridine as starting material ¹HNMR (300 MHz, CDCl₃) δ 8.36 (d, J = 1.8 Hz, 1H), 7.54 (d, J = 2.7 Hz,1H), 7.41 (s, 1H), 7.36-7.32 (m, 3H), 7.16-7.13 (m, 2H), 6.88 (s, 1H),5.38 (s, 2H), 2.33 (s, 3H), 2.16 (s, 3H); ESI >99 MS m/z 304 [M + H]⁺.72 1-(1-benzyl-6- (3,5- dimethylisoxazol- 4-yl)-1H- pyrrolo[3,2-b]pyridin-3-yl)- N,N- dimethylmethanamine

L ¹H NMR (300 MHz, CDCl₃) δ 8.34 (d, J = 1.8 Hz, 1H), 8.30 (s, 1H),7.36-7.32 (m, 4H), 7.21-7.18 (m, 2H), 5.39 (s, 2H), 4.50 (s, 2H), 2.86(s, 6H), 2.32 (s, 3H), 2.16 (s, 3H); ESI MS m/z 361 [M + H]⁺. 98.3 731-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-1H- pyrrolo[2,3- b]pyridin-4-amine

B: using 6- bromo-1H- pyrrolo[2,3- b]pyridin- 4-amine as startingmaterial ¹H NMR (300 MHz, DMSO-d₆) δ 7.31- 7.20 (m, 6H), 6.56 (d, J =3.6 Hz, 1H), 6.35 (s, 1H), 6.32 (s, 2H), 5.35 (s, 2H), 2.49 (s, 3H),2.32 (s, 3H); ESI MS m/z 319 [M + H]⁺; >99 74 3,5-dimethyl-4-(2-methyl-1- (pyridin-4- ylmethyl)-1H- imidazo[4,5- b]pyridin-6-yl)isoxazole

D ¹H NMR (500 MHz, DMSO-d₆) δ 8.53 (dd, J = 3.0, 1.5 Hz, 2H), 8.36 (d, J= 2.0 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.12 (d, J = 6.0 Hz, 2H), 5.62(s, 2H), 2.57 (s, 3H), 2.39 (s, 3H), 2.20 (s, 98.9 3H); ESI m/z 320 [M +H]⁺. 75 1- (cyclopropylmethyl)- 6-(3,5- dimethylisoxazol- 4-yl)-2-methyl-1H- benzo[d]imidazol- 4-amine

F ¹H NMR (500 MHz, CD₃OD) δ 6.70 (s, 1H), 6.44 (d, J = 1.0 Hz, 1H), 4.08(d, J = 6.5 Hz, 2H), 2.61 (s, 3H), 2.40 (s, 3H), 2.25 (s, 3H), 1.30-1.19 (m, 1H), 0.62- 0.53 (m, 2H), 0.45- 0.40 (m, 2H). ESI m/z 297 [M +H]⁺. >99 76 3,5-dimethyl-4- (2-methyl-1-((5- methylthiophen-2-yl)methyl)- 1H-imidazo[4,5- b]pyridin-6- yl)isoxazole

D ¹H NMR (300 MHz, DMSO-d₆) δ 8.34 (d, J = 2.1 Hz, 1H), 8.09 (d, J = 2.1Hz, 1H), 7.04 (d, J = 3.6 Hz, 1H), 6.66 (dd, J = 2.1, 1.2 Hz, 1H), 5.65(s, 2H), 2.66 (s, 3H), 2.44 (s, 3H), 98.1 2.34 (d, J = 0.6 Hz, 3H), 2.27(s, 3H); ESI m/z 339 [M + H]⁺. 77 4-(1-((5- chlorothiophen-2-yl)methyl)-2- methyl-1H- imidazo[4,5- b]pyridin-6-yl)- 3,5-dimethylisoxazole

D ¹H NMR (300 MHz, DMSO-d₆) δ 8.35 (d, J = 2.1 Hz, 1H), 8.12 (d, J = 2.1Hz, 1H), 7.13 (d, J = 3.6 Hz, 1H), 7.02 (d, J = 3.6 Hz, 1H), 5.70 (s,2H), 2.66 (s, 3H), 2.44 (s, 3H), 2.27 (s, 3H); ESI 96.3 m/z 359 [M +H]⁺. 78 5-((6-(3,5- dimethylisoxazol- 4-yl)-2- methyl-1H- imidazo[4,5-b]pyridin-1- yl)methyl) thiophene-2- carbonitrile

D ¹H NMR (500 MHz, DMSO-d₆) δ 8.36 (d, J = 2.0 Hz, 1H), 8.11 (d, J = 2.0Hz, 1H), 7.87 (d, J = 4.0 Hz, 1H), 7.31 (d, J = 4.0 Hz, 1H), 5.86 (s,2H), 2.65 (s, 3H), 2.43 (s, 3H), 2.26 (s, 3H); ESI >99 m/z 350 [M + H]⁺.79 6-(3,5- dimethylisoxazol- 4-yl)-1-(4- fluorobenzyl)- 1H-imidazo[4,5-b]pyridine 4- oxide

N ¹H NMR (300 MHz, DMSO-d₆) δ 8.28 (s, 1H), 8.05 (s, 1H), 7.83 (s, 1H),7.49- 7.45 (m, 2H), 7.13- 7.07 (m, 2H), 6.00 (s, 2H), 2.48 (s, 3H), 2.32(s, 3H); ESI MS m/z 339 [M + H]⁺ >99 80 6-(3,5- dimethylisoxazol-4-yl)-1-(4- fluorobenzyl)- 1H-imidazo[4,5- b]pyridin-5-yl acetate

N: using Example 59 as starting material ¹H NMR (300 MHz, CDCl3) δ 8.34(s, 1H), 8.07 (s, 1H), 7.43-7.38 (m, 2H), 7.12-7.06 (m, 2H), 5.46 (s,2H), 2.31 (s, 3H), 2.19 (s, 3H), 2.16 (s, 3H); ESI MS m/z 381 [M +H]⁺ >99 81 1-benzyl-6-(1,4- dimethyl-1H- pyrazol-5-yl)-2-methyl-4-nitro- 1H- benzo[d]imidazole

F ¹H NMR (300 MHz, DMSO-d₆) δ 8.04 (d, J = 1.5 Hz, 1H), 7.95 (d, J = 1.5Hz, 1H), 7.37-7.29 (m, 4H), 7.23-7.21 (m, 2H), 5.6 (s, 2H), 3.69 (s,3H), 2.68 (s, 3H), 1.93 (s, 3H); ESI m/z 362 [M + H]⁺. 99 821-benzyl-6-(1,4- dimethyl-1H- pyrazol-5-yl)-2- methyl-1H-benzo[d]imidazol- 4-amine

F ¹H NMR (300 MHz, DMSO-d₆) δ 7.36- 7.27 (m, 4H), 7.20- 7.17 (m, 2H),6.62 (d, J = 1.2 Hz, 1H), 6.30 (d, J = 1.2 Hz, 1H), 5.40 (s, 2H), 5.36(s, 2H), 3.62 (s, 3H), 2.51 (s, 3H), 1.89 (s, 3H); ESI m/z 332 [M + H]⁺.98.4 83 4-(1-(4- chlorobenzyl)- 2-methyl-1H- imidazo[4,5-b]pyridin-6-yl)- 3,5- dimethylisoxazole

D ¹H NMR (300 MHz, DMSO-d₆) δ 8.34 (d, J = 1.8 Hz, 1H), 7.98 (d, J = 1.8Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 5.55 (s,2H), 2.59 (s, 3H), 2.40 (s, 3H), 2.22 (s, 3H); ESI >99 m/z 353 [M + H]⁺.84 4-((6-(3,5- dimethylisoxazol- 4-yl)-2- methyl-1H- imidazo[4,5-b]pyridin-1- yl)methyl) phenol

D ¹H NMR (500 MHz, DMSO-d₆) δ 9.45 (s, 1H), 8.31 (d, J = 2.0 Hz, 1H),7.95 (d, J = 2.0 Hz, 1H), 7.09 (d, J = 8.5 Hz, 2H), 6.71 (d, J = 8.5 Hz,2H), 5.39 (s, 2H), 2.61 (s, 3H), 2.40 (s, 3H), >99 2.22 (s, 3H); ESI m/z335 [M + H]⁺. 85 1-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-2- methyl-1H-benzo[d]imidazole- 4- carbonitrile

No general procedure ¹H NMR (500 MHz, CD₃OD) δ 7.63 (d, J = 1.5 Hz, 1H),7.60 (d, J = 1.5 Hz, 1H), 7.38-7.27 (m, 3H), 7.19-7.14 (m, 2H), 5.57 (s,2H), 2.69 (s, 3H), 2.32 (s, 3H), 2.16 (s, 3H); ESI m/z 343 [M + H]⁺. >9986 1-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-2-oxo- 2,3-dihydro-1H-benzo[d]imidazole- 4- carbonitrile

J: using 2- amino-5- bromo- benzonitrile as starting material ¹H NMR(500 MHz, CD₃OD) δ 7.38-7.25 (m, 6H), 7.10 (d, J = 1.5 Hz, 1H), 5.13 (s,2H), 2.27 (s, 3H), 2.09 (s, 3H); ESI m/z 345 [M + H]⁺. >99 871-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-2- morpholino-1H-benzo[d]imidazol- 4-amine

I ¹H NMR (300 MHz, CDCl3) δ 7.35-7.27 (m, 3H), 7.18-7.15 (m, 2H), 6.36(s, 1H), 6.23 (d, J = 0.9 Hz, 1H), 5.22 (s, 2H), 4.29 (br. s, 2H), 3.83(t, J = 4.5 Hz, 4H), 3.25 (br. s, 4H), 2.27 (s, 3H), 2.13 (s, 3H); ESIm/z 404 >99 [M + H]+. 88 1-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-1H-pyrrolo[3,2- b]pyridine-3- carbonitrile

No general procedure ¹H NMR (300 MHz, CDCl3) d 8.55 (s, 1H), 7.98 (s,1H), 7.50 (s, 1H), 7.41- 7.40 (m, 3H), 7.20- 7.15 (m, 2H), 5.42 (s, 2H),2.34 (s, 3H), 2.16 (s, 3H); ESI MS m/z 329 [M + H]+. >99 894-(1-benzyl-3- chloro-1H- pyrrolo[3,2- b]pyridin-6-yl)- 3,5-dimethylisoxazole

No general procedure ¹H NMR (300 MHz, CDCl3) d 8.49 (s, 1H), 7.55 (s,1H), 7.50 (s, 1H), 7.38- 7.36 (m, 3H), 7.18- 7.16 (m, 2H), 5.36 (s, 2H),2.34 (s, 3H), 2.16 (s, 3H); ESI MS m/z 338 [M + H]+. >99 904-amino-1-(4- chlorobenzyl)- 6-(3,5- dimethylisoxazol- 4-yl)-1H-benzo[d]imidazol- 2(3H)-one

E ¹H NMR (500 MHz, CD3OD) δ 7.36-7.28 (m, 4H), 6.40 (d, J = 1.4 Hz, 1H),6.25 (d, J = 1.4 Hz, 1H), 5.03 (s, 2H), 2.28 (s, 3H), 2.12 (s, 3H);HPLC >99%, tR = 13.4 min; ESI m/z 369 [M + H]+. >99 91 1-(4-chlorobenzyl)- 6-(3,5- dimethylisoxazol- 4-yl)-4-nitro- 1H-benzo[d]imidazol- 2(3H)-one

E ¹H NMR (500 MHz, CD3OD) δ 7.80 (d, J = 1.4 Hz, 1H), 7.40- 7.35 (m,4H), 7.24 (d, J = 1.4 Hz, 1H), 5.15 (s, 2H), 2.32 (s, 3H), 2.15 (s, 3H);HPLC 98.7%, tR = 16.5 min; ESI m/z 399 [M + H]+. 98.7 92 4-(1-benzyl-1H-pyrazolo[4,3- b]pyridin-6-yl)- 3,5- dimethylisoxazole

A ¹H NMR (500 MHz, DMSO-d6) δ 8.55 (d, J = 1.8 Hz, 1H), 8.38 (d, J = 0.9Hz, 1H), 8.27 (dd, J = 1.8 Hz, 1.0 Hz, 1H), 7.32- 7.26 (m, 5H), 5.72 (s,2H), 2.45 (s, 3H), 2.27 (s, 3H); ESI m/z 98.7 305 [M + H]+. 93 4-(1-(4-chlorobenzyl)- 1H- pyrazolo[4,3- b]pyridin-6-yl)- 3,5- dimethylisoxazole

A ¹H NMR (500 MHz, CDCl3) δ 8.48 (d, J = 1.0 Hz, 1H), 8.34 (s, 1H), 7.41(s, 1H), 7.33-7.30 (m, 2H), 7.19-7.16 (m, 2H), 5.60 (s, 2H), 2.38 (s,3H), 2.22 (s, 3H); ESI m/z 374 [M + H]+. 98.8 94 1-benzyl-2-methyl-6-(1- methyl-1H- pyrazol-5-yl)- 1H- benzo[d]imidazol- 4-amine

U ¹H NMR (500 MHz, DMSO-d6) δ 7.39 (d, J = 1.5 Hz, 1H), 7.33 (t, J = 7.0Hz, 2H), 7.26 (t, J = 7.0 Hz, 1H), 7.16 (d, J = 7.0 Hz, 2H), 6.76 (d, J= 1.5 Hz, 1H), 6.44 (d, J = 1.5 Hz, 1H), 6.22 (d, J = 2.0 Hz, 1H), 5.41(s, 2H), 5.36 (s, >99 2H), 3.76 (s, 3H), 3.31 (s, 3H); ESI m/z 318 [M +H]+. 95 4-(1-(3,4- dichlorobenzyl)- 2-methy-1H- imidazo[4,5-b]pyridin-6-yl)- 3,5- dimethylisoxazole

D ¹H NMR (500 MHz, DMSO-d6) δ 8.35 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 2.0Hz, 1H), 7.61-7.59 (m, 2H), 7.13 (dd, J = 8.5, 2.0 Hz, 1H), 5.56 (s,2H), 2.61 (s, 3H), 2.40 (s, 3H), 2.22 (s, 3H); ESI m/z 387 [M + H]+. >9996 6-(3,5- dimethylisoxazol- 4-yl)-2- methyl-1-(1- phenylethyl)- 1H-benzo[d]imidazol- 4-amine

K ¹H NMR (300 MHz, DMSO-d6) δ 7.39- 7.28 (m, 5H), 6.24 (s, 1H), 6.15 (s,1H), 5.86 (q, J = 6.9 Hz, 1H), 5.26 (s, 2H), 2.58 (s, 3H), 2.20 (s, 3H),2.02 (s, 3H), 1.86 (d, J = 6.9 Hz, 3H); ESI m/z 347 [M + H]+. >99 972-(azetidin-1- yl)-1-benzyl-6- (3,5- dimethylisoxazol- 4-yl)-1H-benzo[d]imidazol- 4-amine

I ¹H NMR (300 MHz, DMSO-d6) δ 7.34- 7.17 (m, 5H), 6.38 (d, J = 1.5 Hz,1H), 6.27 (d, J = 1.5 Hz, 1H), 5.16 (s, 2H), 5.02 (s, 2H), 4.08 (t, J =7.5 Hz, 4H), 2.34- 2.24 (m, 5H), 2.12 (s, 3H); ESI m/z 374 [M + H]+.98.8 98 3,5-dimethyl-4- (1-(thiophen-3- ylmethyl)-1H- pyrazolo[4,3-b]pyridin-6- yl)isoxazole

A ¹H NMR (500 MHz, CDCl3) δ 8.48 (d, J = 1.7 Hz, 1H), 8.39 (s, 1H), 7.47(s, 1H), 7.34-7.32 (m, 1H), 7.23-7.21 (m, 1H), 6.97 (dd, J = 5.0 Hz, 1.3Hz, 1H), 5.67 (s, 2H), 2.39 (s, 3H), 2.23 (s, 3H); ESI m/z >99 311 [M +H]+. 99 N-(1-benzyl-6- (3,5- dimethylisoxazol- 4-yl)-1H- pyrrolo[3,2-b]pyridin-3- yl)acetamide

No general procedure ¹H NMR (300 MHz, DMSO-d6) d 10.2 (s, 1H), 8.32 (d,J = 1.8 Hz, 1H), 8.23 (s, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.32-7.25 (m,5H), 5.45 (s, 2H), 2.40 (s, 3H), 2.22 (s, 3H), 2.12 (s, 3H); ESI MS m/z361 [M + H]+. 96.7 100 1-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-1H-pyrrolo[3,2- b]pyridin-3- amine

No general procedure ¹H NMR (300 MHz, DMSO-d6) d 8.18 (d, J = 1.8 Hz,1H), 7.82 (d, J = 1.8 Hz, 1H), 7.33-7.21 (m, 5H), 7.06 (s, 1H), 5.30 (s,2H), 4.26 (s, 2H), 2.37 (s, 3H), 2.21 (s, 3H); ESI MS m/z 319 [M + H]⁺.84.2 101 1-(3,4- dichlorobenzyl)- 6-(3,5- dimethylisoxazol- 4-yl)-1H-imidazo[4,5- b]pyridin-2(3H)- one

R ¹H NMR (500 MHz, DMSO-d6) δ 11.83 (s, 1H), 7.92 (d, J = 1.5 Hz, 1H),7.73 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 2.0 Hz,1H), 7.35 (dd, J = 8.5, 2.0 Hz, 1H), 5.05 (s, 2H), 2.37 (s, 3H), 2.19(s, 3H); ESI >99 m/z 389 [M + H]+. 102 1-(4- chlorobenzyl)- 6-(3,5-dimethylisoxazol- 4-yl)-1H- indazol-4-amine

C ¹H NMR (500 MHz, DMSO-d6) δ 8.14 (d, J = 0.8 Hz, 1H), 7.38- 7.34 (m,2H), 7.28- 7.24 (m, 2H), 6.69 (s, 1H), 6.12 (d, J = 1.1 Hz, 1H), 5.94(s, 2H), 5.53 (s, 2H), 2.37 (s, 3H), 2.20 (s, 3H); ESI m/z 353 [M +H]+. >99 103 6-(3,5- dimethylisoxazol- 4-yl)-1-(4- methoxybenzyl)-4-nitro-1H- benzo[d]imidazol- 2(3H)-one

E ¹H NMR (500 MHz, CD3OD) δ 7.78 (d, J = 1.5 Hz, 1H), 7.31 (d, J = 8.7Hz, 2H), 7.23 (d, J = 1.5 Hz, 1H), 6.90 (d, J = 8.7 Hz, 2H), 5.09 (s,2H), 3.75 (s, 3H), 2.32 (s, 3H), 2.14 (s, 3H); ESI m/z 395 [M + H]+. >99104 4-amino-6-(3,5- dimethylisoxazol- 4-yl)-1-(4- methoxybenzyl)- 1H-benzo[d]imidazol- 2(3H)-one

E ¹H NMR (500 MHz, CD3OD) δ 7.26 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6Hz, 2H), 6.39 (d, J = 1.4 Hz, 1H), 6.26 (d, J = 1.4 Hz, 1H), 4.97 (s,2H), 3.74 (s, 3H), 2.28 (s, 3H), 2.12 (s, 3H); HPLC 93.0%, tR = 12.2min; ESI m/z 93.0 365 [M + H]+. 105 1-(4- chlorobenzyl)- 6-(3,5-dimethylisoxazol- 4-yl)-1H- imidazo[4,5- b]pyridin-2(3H)- one

R ¹H NMR (500 MHz, DMSO-d6) δ 11.81 (s, 1H), 7.91 (d, J = 1.5 Hz, 1H),7.45 (d, J = 2.0 Hz, 1H), 7.43- 7.39 (m, 4H), 5.04 (s, 2H), 2.35 (s,3H), 2.17 (s, 3H); ESI m/z 355 [M + H]+. >99 106 6-(3,5-dimethylisoxazol- 4-yl)-1- (thiophen-2- ylmethyl)-1H- imidazo[4,5-b]pyridin-2(3H)- one

R ¹H NMR (500 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.91 (d, J = 2.0 Hz, 1H),7.57 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 5.0, 1.0 Hz, 1H), 7.26 (dd, J =3.5, 1.0 Hz, 1H), 6.97 (dd, J = 5.0, 3.5 98.6 Hz, 1H), 5.24 (s, 2H),2.39 (s, 3H), 2.21 (s, 3H); ESI m/z 327 [M + H]+. 107 1-benzyl-6-(3,5-dimethylisoxazol- 4-yl)-N-ethyl- 1H-imidazo[4,5- b]pyridin-2- amine

Q ¹H NMR (500 MHz, DMSO-d6) δ 7.95 (d, J = 1.5 Hz, 1H), 7.37- 7.31 (m,4H), 7.28- 7.23 (m, 3H), 5.30 (s, 2H), 3.51-4.53 (m, 2H), 2.33 (s, 3H),2.14 (s, 3H), 1.23 (t, J = 7.0 Hz, 3H); ESI >99 m/z 348 [M + H]+. 1083,5-dimethyl-4- (2-methyl-1-(1- phenylethyl)- 1H-imidazo[4,5-b]pyridin-6- yl)isoxazole

No general procedure ¹H NMR (500 MHz, DMSO-d6) δ 8.27 (d, J = 2.0 Hz,1H), 7.44 (d, J = 2.0 Hz, 1H), 7.40-7.36 (m, 4H), 7.33-7.30 (m, 1H),6.01 (q, J = 7.0 Hz, 1H), 2.70 (s, 3H), 2.26 (s, 3H), 2.06 (s, 97.7 3H),1.93 (d, J = 7.0 Hz, 3H); ESI m/z 333 [M + H]+. 109 1-benzyl-6-(3,5-dimethylisoxazol- 4-yl)-N2- (tetrahydro-2H- pyran-4-yl)-1H-benzo[d]imidazole- 2,4-diamine

I ¹H NMR (300 MHz, DMSO-d6) δ 7.34- 7.21 (m, 5H), 6.48 (d, J = 7.8 Hz,1H), 6.29 (d, J = 1.5 Hz, 1H), 6.21 (d, J = 1.5 Hz, 1H), 5.23 (s, 2H),4.83 (s, 2H), 4.04- 3.96 (m, 1H), 3.89 (dd, J = 11.4, 2.7 Hz, 2H), 3.42(td, J = 11.4, 2.7 Hz, 2H), >99 2.28 (s, 3H), 2.11 (s, 3H); 1.98 (dd, J= 12.3, 2.7 Hz, 2H), 1.62-1.49 (m, 2H), ESI m/z 418 [M + H]+. 1106-(3,5- dimethylisoxazol- 4-yl)-4-nitro- 1-(1- phenylethyl)- 1H-benzo[d]imidazol- 2(3H)-one

P ¹H NMR (500 MHz, CD3OD) δ 7.75 (d, J = 1.3 Hz, 1H), 7.44 (d, J = 7.7Hz, 2H), 7.38 (t, J = 7.7 Hz, 2H), 7.31 (t, J = 7.7 Hz, 1H), 6.88 (d, J= 1.3 Hz, 1H), 5.88 (q, J = 7.1 Hz, 1H), 2.20 (s, 3H), 2.02 (s, 3H),1.91 (d, J = 7.2 Hz, 3H); ESI m/z 377 >99 [M − H]+. 111 N-(1-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-2-oxo- 2,3-dihydro-1H- benzo[d]imidazol-4- yl)acetamide

O ¹H NMR (300 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.85 (s, 1H), 7.60-7.46 (m,5H), 7.28 (d, J = 1.2 Hz, 1H), 7.06 (d, J = 1.2 Hz, 1H), 5.22 (s, 2H),2.51 (s, 3H), 2.33 (s, 3H), 2.27 (s, 3H); ESI m/z 377 [M + H]+. 98.8 1126-(3,5- dimethylisoxazol- 4-yl)-1-(1- phenylethyl)- 1H-imidazo[4,5-b]pyridin-2(3H)- one

No general procedure ¹H NMR (500 MHz, DMSO-d6) δ 11.78 (s, 1H), 7.87 (d,J = 2.0 Hz, 1H), 7.44 (d, J = 7.5 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H),7.29 (t, J = 7.5 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H), 5.72 (q, J = >99 7.0Hz, 1H), 2.26 (s, 3H), 2.06 (s, 3H), 1.84 (d, J = 7.0 Hz, 3H); ESI m/z335 [M + H]+. 113 6-(3,5- dimethylisoxazol- 4-yl)-N-ethyl- 1-(1-phenylethyl)- 1H-imidazo[4,5- b]pyridin-2- amine

No general procedure ¹H NMR (500 MHz, DMSO-d6) δ 7.90 (d, J = 2.0 Hz,1H), 7.40- 7.28 (m, 6H), 6.81 (d, J = 2.0 Hz, 1H), 5.84 (q, J = 7.0 Hz,1H), 3.54-3.48 (m, 2H), 2.20 (s, 3H), 1.99 (s, 3H), 1.83 (d, >99 J = 7.0Hz, 3H), 1.27 (t, J = 7.0 Hz, 3H); ESI m/z 362 [M + H]+. 1144-(1-benzyl-6- (3,5- dimethylisoxazol- 4-yl)-1H- imidazo[4,5-b]pyridin-2- yl)morpholine

Q ¹H NMR (500 MHz, CDCl3) δ 8.24 (d, J = 2.0 Hz, 1H), 7.41- 7.34 (m,3H), 7.15 (d, J = 6.5 Hz, 2H), 7.06 (d, J = 1.0 Hz, 1H), 5.26 (s, 2H),3.83 (t, J = 4.5 Hz, 4H), 3.50 (t, J = 4.5 >99 Hz, 4H), 2.29 (s, 3H),2.11 (s, 3H); ESI m/z 390 [M + H]+. 115 4-amino-6-(3,5-dimethylisoxazol- 4-yl)-1-(1- phenylethyl)- 1H- benzo[d]imidazol-2(3H)-one

P ¹H NMR (500 MHz, CD3OD) δ 7.42-7.32 (m, 4H), 7.26 (t, J = 6.9 Hz, 1H),6.35 (s, 1H), 5.94 (s, 1H), 5.78 (q, J = 7.2 Hz, 1H), 2.17 (s, 3H), 2.00(s, 3H), 1.86 (d, J = 7.2 Hz, 3H); ESI m/z 349 [M + H]+. >99 116 4-(1-(cyclobutylmethyl)- 2-methyl- 4-nitro-1H- benzo[d]imidazol- 6-yl)-3,5-dimethylisoxazole

F ¹H NMR (500 MHz, DMSO-d6) δ 8.09 (d, J = 1.5 Hz, 1H), 7.91 (d, J = 1.5Hz, 1H), 4.37 (d, J = 7.0 Hz, 2H), 2.80-2.75 (m, 1H), 2.67 (s, 3H), 2.45(s, 3H), 1.94 (s, 3H), 1.95-1.90 (m, 2H), 1.86-1.77 (m, 4H); ESI m/z 341[M + H]+. >99 117 4-(1- (cyclopentylmethyl)- 2-methyl- 4-nitro-1H-benzo[d]imidazol- 6-yl)-3,5- dimethylisoxazole

F ¹H NMR (500 MHz, DMSO-d6) δ 8.06 (d, J = 1.5 Hz, 1H), 7.91 (d, J = 1.5Hz, 1H), 4.29 (d, J = 7.5 Hz, 2H), 2.68 (s, 3H), 2.45 (s, 3H), 2.37 (m,1H), 2.27 (s, 3H), 1.71-1.58 (m, 4H), 1.57-1.47 (m, 2H), 1.33-1.27 (m,2H); ESI m/z 355 >99 [M + H]+. 118 1- (cyclopropylmethyl)- 6-(3,5-dimethylisoxazol- 4-yl)-1H- imidazo[4,5- b]pyridin-2(3H)- one

No general procedure ¹H NMR (500 MHz, CD3OD) δ 7.90 (d, J = 1.5 Hz, 1H),7.50 (d, J = 1.5 Hz, 1H), 3.81 (d, J = 7.0 Hz, 2H), 2.42 (s, 3H), 2.26(s, 3H), 1.31- 1.20 (m, 1H), 0.60- 0.53 (m, 2H), 0.44- >99 0.38 (m, 2H).ESI m/z 285 [M + H]+. 119 N-(1-benzyl-6- (3,5- dimethylisoxazol-4-yl)-2- (ethylamino)- 1H- benzo[d]imidazol-4- yl)acetamide

O ¹H NMR (300 MHz, DMSO-d6) δ 9.37 (s, 1H), 7.60 (s, 1H), 7.35-7.20 (m,5H), 6.93 (t, J = 5.4 Hz, 1H), 6.80 (s, 1H), 5.29 (s, 2H), 3.57- 3.48(m, 2H), 2.31 (s, 3H), 2.15 (s, 3H), 2.13 (s, 3H), 1.23 (t, J = 7.2 Hz,3H); ESI m/z 404 [M + H]+. 99.0 120 N-(1-benzyl-6- (3,5-dimethylisoxazol- 4-yl)-2- ethoxy-1H- benzo[d]imidazol-4- yl)acetamide

O ¹H NMR (300 MHz, DMSO-d6) δ 9.64 (s, 1H), 7.73 (s, 1H), 7.37-7.27 (m,5H), 7.11 (s, 1H), 5.25 (s, 2H), 4.65 (q, J = 7.2 Hz, 2H), 2.35 (s, 3H),2.18 (s, 3H), 2.16 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H); ESI m/z 405 [M +H]+. >99 121 4-(1-benzyl-4- bromo-2- methyl-1H- benzo[d]imidazol-6-yl)-3,5- dimethylisoxazole

H ¹H NMR (500 MHz, CD3OD) δ 7.40-7.25 (m, 5H), 7.15 (d, J = 7.7 Hz, 2H),5.51 (s, 2H), 2.64 (s, 3H), 2.32 (s, 3H), 2.15 (s, 3H); ESI m/z 396 [M +H]+. >99 122 3-benzyl-5-(3,5- dimethylisoxazol- 4-yl)-1-ethyl- 1H-benzo[d]imidazol- 2(3H)-one

No general procedure ¹H NMR (500 MHz, DMSO-d6) δ 7.37 (d, J = 7.5 Hz,2H), 7.33 (t, J = 7.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 1H), 7.26 (t, J =7.0 Hz, 1H), 7.09 (d, J = 1.5 Hz, 1H), 7.03 (dd, J = 8.0, 1.5 Hz, 1H),5.08 (s, 2H), 3.94 (q, J = 7.0 Hz, 94.6 2H), 2.31 (s, 3H), 2.13 (s, 3H),1.26 (t, J = 7.0 Hz, 3H); ESI m/z 348 [M + H]+. 123 4-(2-(azetidin-1-yl)-1-benzyl-1H- imidazo[4,5- b]pyridin-6-yl)- 3,5- dimethylisoxazole

Q ¹H NMR (500 MHz, CDCl3) δ 8.07 (s, 1H), 7.43-7.37 (m, 3H), 7.13 (d, J= 6.5 Hz, 2H), 7.05 (s, 1H), 5.23 (s, 2H), 4.49 (t, J = 7.0 Hz, 4H),2.54 (quin, J = 7.5 Hz, 2H), 2.30 (s, 3H), >99 2.10 (s, 3H); ESI m/z 360[M + H]+. 124 1-((5- chlorothiophen- 2-yl)methyl)-6- (3,5-dimethylisoxazol- 4-yl)-1H- imidazo[4,5- b]pyridin-2(3H)- one

R ¹H NMR (500 MHz, DMSO-d6) δ 11.81 (s, 1H), 7.92 (d, J = 2.0 Hz, 1H),7.63 (d, J = 1.5 Hz, 1H), 7.15 (d, J = 4.0 Hz, 1H), 6.99 (s, J = 4.0 Hz,1H), 5.17 (s, 2H), 2.40 (s, 3H), 2.22 (s, >99 3H); ESI m/z 361 [M + H]+.125 (S)-3,5- dimethyl-4-(2- methyl-4-nitro- 1-(1- phenylethyl)- 1H-benzo[d]imidazol- 6- yl)isoxazole

S ¹H NMR (300 MHz, DMSO-d6) d 7.87 (d, J = 1.5 Hz, 1H), 7.42- 7.30 (m,6H), 6.11 (q, J = 7.2 Hz, 1H), 2.74 (s, 3H), 2.23 (s, 3H), 2.04 (s, 3H),1.94 (d, J = 6.9 Hz, 3H); ESI MS m/z 377 [M + H]+. >99 126 (R)-3,5-dimethyl-4-(2- methyl-4-nitro- 1-(1- phenylethyl)- 1H- benzo[d]imidazol-6- yl)isoxazole

S ¹H NMR (300 MHz, DMSO-d6) d 7.87 (d, J = 1.5 Hz, 1H), 7.42- 7.30 (m,6H), 6.11 (q, J = 7.2 Hz, 1H), 2.74 (s, 3H), 2.23 (s, 3H), 2.04 (s, 3H),1.94 (d, J = 6.9 Hz, 3H); ESI MS m/z 377 [M + H]+. 98.3 127 6-(3,5-dimethylisoxazol- 4-yl)-N-ethyl- 4-nitro-1-(1- phenylethyl)- 1H-benzo[d]imidazol- 2-amine

No general procedure ¹H NMR (500 MHz, CD3OD) δ 7.70 (d, J = 1.5 Hz, 1H),7.45- 7.30 (m, 5H), 6.72 (d, J = 1.5 Hz, 1H), 5.86 (q, J = 7.0 Hz, 1H),3.72 (q, J = 7.2 Hz, 2H), 2.17 (s, 3H), 1.98 (s, 3H), 1.90 (d, J = 7.0Hz, 3H), 1.36 (t, J = 7.2 Hz, 3H); ESI m/z 406 96.3 [M + H]+. 1284-(1-benzyl-2- ethyl-1H- imidazo[4,5- b]pyridin-6-yl)- 3,5-dimethylisoxazole

D ¹H NMR (500 MHz, CDCl3) δ 8.42 (d, J = 1.7 Hz, 1H), 7.39- 7.33 (m,3H), 7.30 (d, J = 1.6 Hz, 1H), 7.10-7.09 (m, 2H), 5.41 (s, 2H), 3.08 (q,J = 7.5 Hz, 2H), 2.32 (s, 3H), 2.15 (s, 3H), >99 1.51 (t, J = 7.5 Hz,3H); ESI m/z 333 [M + H]+. 129 4-amino-6-(3,5- dimethylisoxazol-4-yl)-1-(4- hydroxybenzyl)- 1H- benzo[d]imidazol- 2(3H)-one

No general procedure ¹H NMR (500 MHz, CD3OD) δ 7.17 (d, J = 8.6 Hz, 2H),6.72 (d, J = 8.6 Hz, 2H), 6.39 (d, J = 1.3 Hz, 1H), 6.26 (d, J = 1.3 Hz,1H), 4.94 (s, 2H), 2.28 (s, 3H), 2.12 (s, 3H); ESI m/z 351 [M + H]+. >99130 N-(2-(azetidin- 1-yl)-1-benzyl- 6-(3,5- dimethylisoxazol- 4-yl)-1H-benzo[d]imidazol- 4- yl)acetamide

O ¹H NMR (300 MHz, DMSO-d6) δ 7.69 (s, 1H), 7.36-7.16 (m, 6H), 6.92 (s,1H), 5.26 (s, 2H), 4.18 (t, J = 7.5 Hz, 4H), 2.35- 2.27 (m, 5H), 2.15(s, 3H), 2.14 (s, 3H); ESI m/z 416 [M + H]+. 98.2 131 1-(cyclopropylmethyl)- 6-(3,5- dimethylisoxazol- 4-yl)-N-ethyl-1H-imidazo[4,5- b]pyridin-2- amine

No general procedure ¹H NMR (500 MHz, CDCl3) δ 7.93 (d, J = 2.0 Hz, 1H),7.48 (d, J = 1.5 Hz, 1H), 3.98 (d, J = 6.5 Hz, 2H), 3.57 (q, J = 7.0 Hz,2H), 2.42 (s, 3H), 2.26 (s, 3H), 1.30 (t, >99 J = 7.0 Hz, 3H), 1.29-1.19 (m, 1H), 0.59- 0.52 (m, 2H), 0.45- 0.39 (m, 2H). ESI m/z 312 [M +H]+. 132 1- (cyclobutylmethyl)- 6-(3,5- dimethylisoxazol- 4-yl)-2-methyl-1H- benzo[d]imidazol- 4-amine

F ¹H NMR (500 MHz, CD3OD) δ 6.70 (d, J = 1.5 Hz, 1H), 6.43 (d, J = 1.5Hz, 1H), 4.18 (d, J = 7.0 Hz, 2H), 2.85-2.79 (m, 1H), 2.60 (s, 3H), 2.40(s, 3H), 2.25 (s, 3H), 2.06-1.98 (m, 2H), 1.94-1.82 (m, 4H); ESI m/z 31198.5 [M + H]+. 133 1- (cyclopentylmethyl)- 6-(3,5- dimethylisoxazol-4-yl)-2- methyl-1H- benzo[d]imidazol- 4-amine

F ¹H NMR (500 MHz, CD3OD) δ 6.69 (d, J = 1.5 Hz, 1H), 6.44 (d, J = 1.5Hz, 1H), 4.10 (d, J = 7.5 Hz, 2H), 2.61 (s, 3H), 2.50-2.40 (m, 1H), 2.40(s, 3H), 2.25 (s, 3H), 1.80-1.65 (m, 4H), 1.64-1.55 (m, 2H), 1.42-1.28(m, >99 2H); ESI m/z 325 [M + H]+. 134 6-(3,5- dimethylisoxazol-4-yl)-N2- ethyl-1-(1- phenylethyl)- 1H- benzo[d]imidazole- 2,4-diamine

No general procedure ¹H NMR (500 MHz, CD3OD) δ 7.40-7.25 (m, 5H), 6.31(d, J = 1.5 Hz, 1H), 5.92 (d, J = 1.5 Hz, 1H), 5.72 (q, J = 6.9 Hz, 1H),3.53 (q, J = 7.2 Hz, 2H), 2.15 (s, 3H), 1.99 (s, 3H), 1.86 (d, J = 7.0Hz, 3H), 1.33 (t, J = 7.2 Hz, 3H); >99 ESI m/z 376 [M + H]+. 1354-(1-benzyl-4- nitro-2- (pyrrolidin-1- yl)-1H- benzo[d]imidazol-6-yl)-3,5- dimethylisoxazole

I ¹H NMR (300 MHz, DMSO-d6) δ 7.74 (d, J = 1.5 Hz, 1H), 7.55 (d, J = 1.5Hz, 1H), 7.37-7.24 (m, 3H), 7.15-7.12 (m, 2H), 5.60 (s, 2H), 3.69 (t, J= 6.9 Hz, 4H), 2.34 (s, 3H), 2.16 (s, 3H), 1.92-1.88 (m, 4H); ESI m/z418 [M + H]+. 96.8 136 4-(1-benzyl-2- (4- methylpiperazin-1-yl)-4-nitro- 1H- benzo[d]imidazol- 6-yl)-3,5- dimethylisoxazole

I ¹H NMR (300 MHz, DMSO-d6) δ 7.82 (d, J = 1.5 Hz, 1H), 7.59 (d, J = 1.5Hz, 1H), 7.37-7.28 (m, 3H), 7.22-7.19 (m, 2H), 5.45 (s, 2H), 3.40 (t, J= 4.8 Hz, 4H), 2.45 (t, J = 4.5 Hz, 4H), 2.33 (s, 3H), 2.21 (s, 3H),2.13 (s, 3H); ESI m/z 447 [M + H]+. 98.5 137 1-benzyl-6-(3,5-dimethylisoxazol- 4-yl)-N-(2- methoxyethyl)- 4-nitro-1H-benzo[d]imidazol- 2-amine

I ¹H NMR (300 MHz, DMSO-d6) δ 7.84 (t, J = 5.1 Hz, 1H), 7.67 (d, J = 1.5Hz, 1H), 7.44 (d, J = 1.5 Hz, 1H), 7.36-7.25 (m, 5H), 5.41 (s, 2H),3.73-3.67 (m, 2H), 3.61-3.57 (m, 2H), 3.27 (s, 3H), 2.33 (s, 3H), 2.15(s, 3H); ESI m/z 422 [M + H]+. 97.4 138 4-(1-benzyl-2- cyclopropyl-1H-imidazo[4,5- b]pyridin-6-yl)- 3,5- dimethylisoxazole

No general procedure ¹H NMR (500 MHz, DMSO-d6) δ 8.29 (d, J = 2.1 Hz,1H), 7.95 (d, J = 2.0 Hz, 1H), 7.37-7.33 (m, 2H), 7.30-7.28 (m, 3H),5.67 (s, 2H), 2.38 (s, 3H), 2.37-2.35 (m, 1H), 2.20 (s, 3H), >991.13-1.11 (m, 4H); ESI m/z 345 [M + H]+. 139 1-benzyl-6-(3,5-dimethylisoxazole- 4-yl)-N2-(2- methoxyethyl)- 1H- benzo[d]imidazole-2,4-diamine

I ¹H NMR (300 MHz, DMSO-d6) δ 7.33- 7.20 (m, 5H), 6.76 (t, J = 5.1 Hz,1H), 6.32 (d, J = 1.2 Hz, 1H), 6.21 (d, J = 1.5 Hz, 1H), 5.21 (s, 2H),4.84 (s, 2H), 3.56 (s, 4H), 3.28 (s, 3H), 2.29 (s, 3H), 2.11 (s, 3H);ESI m/z 392 97.5 [M + H]+. 140 1-benzyl-6-(3,5- dimethylisoxazol-4-yl)-2- (pyrrolidin-1- yl)-1H- benzo[d]imidazol- 4-amine

I ¹H NMR (300 MHz, DMSO-d6) δ 7.34- 7.24 (m, 3H), 7.18- 7.15 (m, 2H),6.35 (d, J = 1.5 Hz, 1H), 6.28 (d, J = 1.2 Hz, 1H), 5.42 (s, 2H), 4.98(s, 2H), 3.47 (t, J = 6.9 Hz, 4H), 2.29 (s, 3H), 2.12 (s, 3H), 1.88-1.84(m, 4H); >99 ESI m/z 388 [M + H]+. 141 1-benzyl-6-(3,5-dimethylisoxazol- 4-yl)-2-(4- methylpiperazin- 1-yl)-1H-benzo[d]imidazol- 4-amine

I ¹H NMR (300 MHz, DMSO-d6) δ 7.34- 7.20 (m, 5H), 6.35 (d, J = 1.5 Hz,1H), 6.29 (d, J = 1.2 Hz, 1H), 5.22 (s, 2H), 5.16 (s, 2H), 3.14 (t, J =4.8 Hz, 4H), 2.50 (t, J = 4.5 Hz, 4H), 2.27 (s, 3H), 2.23 (s, 3H), 2.10(s, 3H); ESI 97.8 m/z 417 [M + H]+. 142 1-benzyl-N6- (3,5-dimethylisoxazol- 4-yl)-2- methyl-1H- benzo[d]imidazole- 4,6-diamine

No general procedure ¹H NMR (500 MHz, DMSO-d6) δ 7.31 (t, J = 7.5 Hz,2H), 7.25 (t, J = 7.5 Hz, 1H), 7.04 (d, J = 7.5 Hz, 2H), 6.69 (s, 1H),5.73 (d, J = 2.0 Hz, 1H), 5.60 (d, J = 2.0 Hz, 1H), 5.18 (s, 2H), 5.05(s, 2H), 2.38 (s, 3H), 2.13 (s, 3H), 1.92 (s, 3H); ESI m/z >99 348 [M +H]+. 143 (S)-6-(3,5- dimethylisoxazol- 4-yl)-2- methyl-1-(1-phenylethyl)- 1H- benzo[d]imidazol- 4-amine

S ¹H NMR (300 MHz, DMSO-d6) d 7.39- 7.26 (m, 5H), 6.23 (d, J = 1.5 Hz,1H), 6.14 (d, J = 1.2 Hz, 1H), 5.86 (q, J = 7.2 Hz, 1H), 5.26 (s, 2H),2.58 (s, 3H), 2.20 (s, 3H), 2.02 (s, 3H), 1.86 (d, J = 6.9 Hz, 3H); ESIMS m/z 347 >99 [M + H]+. 144 (R)-6-(3,5- dimethylisoxazol- 4-yl)-2-methyl-1-(1- phenylethyl)- 1H- benzo[d]imidazol- 4-amine

S ¹H NMR (300 MHz, DMSO-d6) d 7.39- 7.26 (m, 5H), 6.23 (d, J = 1.5 Hz,1H), 6.14 (d, J = 1.2 Hz, 1H), 5.86 (q, J = 7.2 Hz, 1H), 5.26 (s, 2H),2.58 (s, 3H), 2.20 (s, 3H), 2.02 (s, 3H), 1.86 (d, J = 6.9 Hz, 3H); ESIMS m/z 347 >99 [M + H]+. 145 1- (cyclopropylmethyl)- 6-(3,5-dimethylisoxazol- 4-yl)-4-nitro- 1H- benzo[d]imidazol- 2(3H)-one

No general procedure ¹H NMR (500 MHz, CD3OD) δ 7.82 (d, J = 1.5 Hz, 1H),7.52 (d, J = 1.0 Hz, 1H), 3.87 (d, J = 7.0 Hz, 2H), 2.45 (s, 3H), 2.29(s, 3H), 1.30- 1.18 (m, 1H), 0.60- 0.52 (m, 2H), 0.47- 0.43 (m, 2H). ESIm/z 329 [M + H]+. >99 146 1-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-N-methyl-1H- imidazo[4,5- b]pyridin-2- amine

Q ¹H NMR (500 MHz, DMSO-d6) δ 7.96 (d, J = 2.0 Hz, 1H), 7.42 (d, J = 1.0Hz, 1H), 7.40-7.36 (br s, 1H), 7.35-7.31 (m, 2H), 7.28-7.23 (m, 3H),5.29 (s, 2H), 3.00 (d, J = 4.6 Hz, 3H), 2.34 >99 (s, 3H), 2.15 (s, 3H);ESI m/z 334 [M + H]+. 147 N,1-dibenzyl-6- (3,5- dimethylisoxazol-4-yl)-4-nitro- 1H- benzo[d]imidazol- 2-amine

I ¹H NMR (300 MHz, DMSO-d6) δ 8.25 (t, J = 5.4 Hz, 1H), 7.69 (s, 1H),7.50 (s, 1H), 7.39-7.22 (m, 10H), 5.44 (s, 2H), 4.77 (d, J = 5.7 Hz,2H), 2.35 (s, 3H), 2.16 (s, 3H); ESI m/z 454 [M + H]+. 97.9 1481-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-4-nitro- N-(pyridin-3-ylmethyl)-1H- benzo[d]imidazol- 2-amine

I ¹H NMR (300 MHz, DMSO-d6) δ 8.65 (d, J = 1.5 Hz, 1H), 8.47 (dd, J =4.8, 1.5 Hz, 1H), 8.30 (t, J = 6.0 Hz, 1H), 7.81 (dt, J = 7.8, 1.8 Hz,1H), 7.70 (d, J = 1.5 Hz, 1H), 7.51 (d, J = 1.5 Hz, 1H), 7.38-7.21 (m,6H), 5.42 (s, 2H), 4.76 (d, J = 5.7 Hz, 98.5 2H), 2.34 (s, 3H), 2.16 (s,3H); ESI m/z 455 [M + H]+. 149 1-benzyl-6-(3,5- dimethylisoxazol-4-yl)-N- methyl-4-nitro- 1H- benzo[d]imidazol- 2-amine

I ¹H NMR (300 MHz, DMSO-d6) δ 7.68- 7.66 (m, 2H), 7.45 (d, J = 1.5 Hz,1H), 7.37-7.22 (m, 5H), 5.37 (s, 2H), 3.06 (d, J = 4.8 Hz, 3H), 2.34 (s,3H), 2.16 (s, 3H); ESI m/z 378 [M + H]+. >99 150 1-benzyl-6-(3,5-dimethylisoxazol- 4-yl)-3- methyl-4-nitro- 1H- benzo[d]imidazol-2(3H)-one

No general procedure ¹H NMR (300 MHz, CDCl3) δ 7.48 (d, J = 1.5 Hz, 1H),7.35- 7.30 (m, 5H), 6.84 (d, J = 1.5 Hz, 1H), 5.15 (s, 2H), 3.65 (s,3H), 2.26 (s, 3H), 2.09 (s, 3H); ESI m/z 379 [M + H]+. >99 1511-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-N2- methyl-1H-benzo[d]imidazole- 2,4-diamine

I ¹H NMR (300 MHz, DMSO-d6) δ 7.33- 7.20 (m, 5H), 6.63 (br. s, 1H), 6.32(s, 1H), 6.23 (s, 1H), 5.17 (s, 2H), 4.86 (s, 2H), 2.94 (d, J = 4.5 Hz,3H), 2.29 (s, 3H), 2.12 (s, 3H); ESI m/z 348 [M + H]+. >99 152N2,1-dibenzyl- 6-(3,5- dimethylisoxazol- 4-yl)-1H- benzo[d]imidazole-2,4-diamine

I ¹H NMR (300 MHz, DMSO-d6) δ 7.37- 7.22 (m, 11H), 6.35 (s, 1H), 6.22(s, 1H), 5.26 (s, 2H), 4.83 (s, 2H), 4.65 (d, J = 5.7 Hz, 2H), 2.29 (s,3H), 2.12 (s, 3H); ESI m/z 424 [M + H]+. >99 153 N,1-dibenzyl-6- (3,5-dimethylisoxazol- 4-yl)-1H- imidazo[4,5- b]pyridin-2- amine

Q ¹H NMR (500 MHz, DMSO-d6) δ 7.98- 7.95 (m, 2H), 7.44 (d, J = 2.0 Hz,1H), 7.36-7.24 (m, 10H), 5.37 (s, 2H), 4.68 (d, J = 5.9 Hz, 2H), 2.34(s, 3H), 2.15 (s, 3H); ESI m/z 410 [M + H]+. >99 154 1-benzyl-2-methyl-6-(1- methyl-1H- pyrazol-5-yl)- 1H-imidazo[4,5- b]pyridine

No general procedure ¹H NMR (500 MHz, DMSO-d6) δ 8.48 (d, J = 2.0 Hz,1H), 8.14 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.35 (t, J =7.0 Hz, 2H), 7.29 (t, J = 7.0 Hz, 1H), 7.21 (d, J = 7.0 Hz, 2H), 6.4699.0 (d, J = 2.0 Hz, 1H), 5.57 (s, 2H), 3.83 (s, 3H), 2.60 (s, 3H); ESIm/z 304 [M + H]+. 155 N-(1-benzyl-2- methyl-1H- imidazo[4,5-b]pyridin-6-yl)- 3,5- dimethylisoxazol- 4-amine

No general procedure ¹H NMR (500 MHz, DMSO-d6) δ 7.88 (d, J = 2.5 Hz,1H), 7.34- 7.30 (m, 3H), 7.27 (t, J = 7.0 Hz, 1H), 7.05 (d, J = 7.0 Hz,2H), 6.71 (d, J = 2.5 Hz, 1H), 5.38 (s, 2H), 2.47 (s, 3H), 2.14 (s, 3H),1.92 (s, 3H); ESI >99 m/z 334 [M + H]+. 156 4-benzyl-6-(3,5-dimethylisoxazol- 4-yl)-3,4- dihydroquinoxalin- 2(1H)-one

No general procedure ¹H NMR (500 MHz, DMSO-d6) δ 10.58 (s, 1H),7.38-7.34 (m, 4H), 7.30-7.23 (m, 1H), 6.87 (d, J = 7.9 Hz, 1H), 6.65 (d,J = 7.9 Hz, 1H), 6.51 (s, 1H), 4.46 (s, 2H), 3.86 (s, 2H), 2.15 (s, 3H),1.97 (s, 3H); ESI m/z 334 [M + H]+. >99 157 1-benzyl-6-(3,5-dimethylisoxazol- 4-yl)-N2- (pyridin-3- ylmethyl)-1H- benzo[d]imidazole-2,4-diamine

I ¹H NMR (300 MHz, DMSO-d6) δ 8.62 (d, J = 1.5 Hz, 1H), 8.44 (dd, J =4.8, 1.5 Hz, 1H), 7.78 (dt, J = 7.8, 1.8 Hz, 1H), 7.35- 7.20 (m, 7H),6.35 (d, J = 1.5 Hz, 1H), 6.22 (d, J = 1.5 Hz, 1H), 5.24 (s, 2H), 4.87(s, 2H), 4.64 (d, 97.9 J = 5.7 Hz, 2H), 2.29 (s, 3H), 2.12 (s, 3H); ESIm/z 425 [M + H]+. 158 4-(1-benzyl-4- fluoro-2- methyl-1H-benzo[d]imidazol- 6-yl)-3,5- dimethylisoxazole

S ¹H NMR (300 MHz, DMSO-d6) d 7.38- 7.26 (m, 4H), 7.22- 7.19 (m, 2H),7.03 (dd, J = 11.7, 1.2 Hz, 1H), 5.53 (s, 2H), 2.57 (s, 3H), 2.36 (s,3H), 2.19 (s, 3H); ESI MS m/z 336 [M + H]+. >99 159 1-(cyclopropylmethyl)- 6-(3,5- dimethylisoxazol- 4-yl)-N-ethyl-4-nitro-1H- benzo[d]imidazol- 2-amine

No general procedure ¹H NMR (500 MHz, CDCl3) δ 7.78 (d, J = 1.5 Hz, 1H),7.44 (d, J = 1.5 Hz, 1H), 4.03 (d, J = 6.5 Hz, 2H), 3.67 (q, J = 7.0 Hz,2H), 2.44 (s, 3H), 2.29 (s, 3H), 1.33 (t, J = 7.0 Hz, 3H), 1.30- 1.18(m, 1H), 0.60- 0.52 (m, 2H), 0.47- >99 0.41 (m, 2H). ESI m/z 356 [M +H]+. 160 1- (cyclopropylmethyl)- 6-(3,5- dimethylisoxazol- 4-yl)-N2-ethyl-1H- benzo[d]imidazole- 2,4-diamine

No general procedure ¹H NMR (500 MHz, CD3OD) δ 6.49 (d, J = 1.5 Hz, 1H),6.37 (d, J = 1.5 Hz, 1H), 3.88 (d, J = 6.5 Hz, 2H), 3.48 (q, J = 7.0 Hz,2H), 2.39 (s, 3H), 2.24 (s, 3H), 1.30 (t, J = 7.5 Hz, 3H), 1.28- 1.18(m, 1H), 0.53- >99 0.48 (m, 2H), 0.40- 0.35 (m, 2H). ESI m/z 326 [M +H]+. 161 4-amino-1- (cyclopropylmethyl)- 6-(3,5- dimethylisoxazol-4-yl)-1H- benzo[d]imidazol- 2(3H)-one

No general procedure ¹H NMR (500 MHz, CD3OD) δ 6.49 (d, J = 1.5 Hz, 1H),6.42 (d, J = 1.5 Hz, 1H), 3.75 (d, J = 6.5 Hz, 2H), 2.39 (s, 3H), 2.24(s, 3H), 1.28- 1.18 (m, 1H), 0.56- 0.48 (m, 2H), 0.44- 0.39 (m, 2H). ESI97.4 m/z 299 [M + H]+. 162 4-amino-1- benzyl-6-(3,5- dimethylisoxazol-4-yl)-3- methyl-1H- benzo[d]imidazol- 2(3H)-one

No general procedure ¹H NMR (300 MHz, DMSO-d6) δ 7.36- 7.24 (m, 5H),6.40 (d, J = 1.5 Hz, 1H), 6.39 (d, J = 1.8 Hz, 1H), 5.08 (s, 2H), 4.99(s, 2H), 3.62 (s, 3H), 2.29 (s, 3H), 2.12 (s, 3H); ESI m/z 349 [M +H]+. >99 163 1-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-4- fluoro-1H-benzo[d]imidazol- 2(3H)-one

J ¹H NMR (300 MHz, DMSO-d6) d 11.7 (s, 1H), 7.39-7.27 (m, 5H), 6.96 (d,J = 1.2 Hz, 1H), 6.92 (s, 1H), 5.04 (s, 2H), 2.32 (s, 3H), 2.14 (s, 3H);ESI MS m/z 338 [M + H]+. 90.3 164 N-(1-benzyl-6- (3,5- dimethylisoxazol-4-yl)-3- methyl-2-oxo- 2,3-dihydro-1H- benzo[d]imidazol- 4- yl)acetamide

O ¹H NMR (300 MHz, DMSO-d6) δ 9.77 (s, 1H), 7.41-7.24 (m, 5H), 7.03 (d,J = 1.5 Hz, 1H), 6.77 (d, J = 1.5 Hz, 1H), 5.08 (s, 2H), 3.46 (s, 3H),2.31 (s, 3H), 2.14 (s, 3H), 2.08 (s, 3H); ESI m/z 391 [M + H]+. >99 1654-(1-benzyl-2- (4- methylpiperazin- 1-yl)-1H- imidazo[4,5-b]pyridin-6-yl)- 3,5- dimethylisoxazole

Q ¹H NMR (500 MHz, DMSO-d6) δ 8.17 (d, J = 2.1 Hz, 1H), 7.57 (d, J = 2.1Hz, 1H), 7.36-7.31 (m, 2H), 7.29-7.25 (m, 1H), 7.22-7.19 (m, 2H), 5.36(s, 2H), 3.35- 3.32 (m, 4H), 2.46- >99 2.44 (m, 4H), 2.32 (s, 3H), 2.22(s, 3H), 2.14 (s, 3H); ESI m/z 403 [M + H]+. 166 4-benzyl-6-(1-methyl-1H- pyrazol-5-yl)- 3,4- dihydroquinoxalin- 2(1H)-one

No general procedure ¹H NMR (500 MHz, DMSO-d6) δ 10.62 (s, 1H),7.37-7.33 (m, 5H), 7.29-7.25 (m, 1H), 6.90 (d, J = 7.9 Hz, 1H), 6.80(dd, J = 7.9, 1.8 Hz, 1H), 6.70 (d, J = 1.6 Hz, 1H), 6.18 (d, J = 1.8Hz, 1H), 4.49 (s, 2H), 3.83 (s, 2H), 3.58 (s, 3H); ESI m/z >99 319 [M +H]+. 167 1-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-N-(2- methoxyethyl)-1H-imidazo[4,5- b]pyridin-2- amine

Q ¹H NMR (500 MHz, DMSO-d6) δ 7.95 (d, J = 2.0 Hz, 1H), 7.54- 7.50 (m,1H), 7.40 (d, J = 2.0 Hz, 1H), 7.34-7.30 (m, 2H), 7.28-7.23 (m, 3H),5.32 (s, 2H), 3.64- 3.59 (m, 2H), 3.58- 3.55 (m, 2H), 3.29 (s, 3H), 2.33(s, 3H), >99 2.15 (s, 3H); ESI m/z 378 [M + H]+. 168 4-(1-benzyl-2-methyl-4- (methylsulfonyl)- 1H- benzo[d]imidazol- 6-yl)-3,5-dimethylisoxazole

No general procedure ¹H NMR (300 MHz, CDCl3) δ 7.75 (d, J = 1.5 Hz, 1H),7.37- 7.33 (m, 3H), 7.24 (d, J = 1.5 Hz, 1H), 7.11-7.08 (m, 2H), 5.39(s, 2H), 3.54 (s, 3H), 2.73 (s, 3H), 2.31 (s, 3H), 2.16 (s, 3H); ESI m/z396 [M + H]+. 92.3 169 1-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-N-(pyridin-4- ylmethyl)-1H- imidazo[4,5- b]pyridin-2- amine

Q ¹H NMR (300 MHz, DMSO-d6) δ 8.50- 8.46 (m, 2H), 8.08 (t, J = 5.9 Hz,1H), 7.97 (d, J = 2.0 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.40-7.25 (m,7H), 5.40 (s, 2H), 4.69 (d, J = 5.9 Hz, 2H), 2.34 (s, 3H), 98.0 2.16 (s,3H); ESI m/z 411 [M + H]+. 170 1-benzyl-6-(3,5- dimethylisoxazol-4-yl)-N- (tetrahydro-2H- pyran-4-yl)-1H- imidazo[4,5- b]pyridin-2- amine

Q ¹H NMR (300 MHz, DMSO-d6) δ 7.96 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 2.0Hz, 1H), 7.37-7.22 (m, 6H), 5.35 (s, 2H), 4.14- 3.98 (m, 1H), 3.95- 3.86(m, 2H), 3.50- 3.38 (m, 2H), 2.33 (s, 3H), 2.14 (s, 3H), 2.00-1.91 (m,2H), 1.68-1.50 (m, 2H); >99 ESI m/z 404 [M + H]+. 171 1-benzyl-6-(1-methyl-1H- pyrazol-5-yl)- 1H-imidazo[4,5- b]pyridin-2(3H)- one

No general procedure ¹H NMR (500 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.04 (d,J = 1.5 Hz, 1H), 7.57 (d, J = 1.5, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.38(d, J = 7.5 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.27 (t, J = 7.0 >99 Hz,1H), 6.37 (d, J = 1.5 Hz, 1H), 5.06 (s, 2H), 3.77 (s, 3H); ESI m/z 306[M + H]+. 172 (S)-6-(3,5- dimethylisoxazol- 4-yl)-4-nitro- 1-(1-phenylethyl)- 1H- benzo[d]imidazol- 2(3H)-one

P ¹H NMR (300 MHz, DMSO-d6) d 12.1 (s, 1H), 7.68 (d, J = 1.5 Hz, 1H),7.45-7.29 (m, 5H), 7.13 (d, J = 1.2 Hz, 1H), 5.79 (q, J = 7.2 Hz, 1H),2.25 (s, 3H), 2.04 (s, 3H), 1.88 (d, J = 7.2 Hz, 3H); ESI MS m/z 379[M + H]+. >99 173 1-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-2- methyl-1H-benzo[d]imidazol- 4-ol

No general procedure ¹H NMR (500 MHz, DMSO-d6) δ 9.84 (s, 1H), 7.33 (t,J = 7.6 Hz, 2H), 7.26 (t, J = 7.3 Hz, 1H), 7.18 (d, J = 7.1 Hz, 2H),6.86 (d, J = 1.3 Hz, 1H), 6.47 (d, J = 1.3 Hz, 1H), 5.42 (s, 2H), 2.52(s, 3H), 2.33 (s, 3H), 2.15 (s, 3H); ESI >99 m/z 334 [M + H]+. 174(R)-4-benzyl-6- (3,5- dimethylisoxazol- 4-yl)-3- methyl-3,4-dihydroquinoxalin- 2(1H)-one

No general procedure ¹H NMR (500 MHz, DMSO-d6) δ 10.53 (s, 1H),7.37-7.32 (m, 4H), 7.26-7.23 (m, 1H), 6.88 (d, J = 7.9 Hz, 1H), 6.66(dd, J = 7.9, 1.7 Hz, 1H), 6.42 (d, J = 1.5 Hz, 1H), 4.54 (d, J = 15.6Hz, 1H), 4.37 (d, J = 15.7 Hz, 1H), 98.7 3.98 (q, J = 6.7 Hz, 1H), 2.11(s, 3H), 1.93 (s, 3H), 1.12 (d, J = 6.7 Hz, 3H); ESI m/z 348 [M + H]+.175 4-(1-benzyl-6- (1-methyl-1H- pyrazol-5-yl)- 1H-imidazo[4,5-b]pyridin-2- yl)morpholine

Q ¹H NMR (500 MHz, DMSO-d6) δ 8.33 (d, J = 1.5 Hz, 1H), 7.74 (d, J = 1.5Hz, 1H), 7.46 (d, J = 1.5 Hz, 1H), 7.34 (t, J = 7.5 Hz, 2H), 7.27 (t, J= 7.5 Hz, 1H), 7.20 (d, J = 7.0 Hz, 2H), 6.38 95.6 (d, J = 1.5 Hz, 1H),5.42 (s, 2H), 3.76 (s, 3H), 3.72 (t, J = 4.5 Hz, 4H), 3.34 (t, J = 4.5Hz, 4H); ESI m/z 375 [M + H]+. 176 1-benzyl-6-(1- methyl-1H-pyrazol-5-yl)-N- (tetrahydro-2H- pyran-4-yl)-1H- imidazo[4,5-b]pyridin-2- amine

Q ¹H NMR (500 MHz, DMSO-d6) δ 8.10 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 2.0Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.33 (t, J = 7.0 Hz, 2H), 7.28-7.21(m, 4H), 6.32 (d, J = 1.5 Hz, 1H), 5.37 (s, 2H), 4.11-4.04 (m, 1H), 3.91(dd, J = 10.0, 2.0 Hz, 2H), >99 3.75 (s, 3H), 3.44 (td, J = 12.0, 2.0Hz, 2H), 1.96 (dd, J = 12.5, 2.0 Hz, 2H), 1.60 (qd, J = 12.0, 4.0 Hz,2H); ESI m/z 389 [M + H]+. 177 4-amino-1- benzyl-6-(3,5-dimethylisoxazol- 4-yl)-1H- benzo[d]imidazole- 2(3H)- thione

No general procedure ¹H NMR (300 MHz, DMSO-d6) δ 12.56 (s, 1H),7.45-7.42 (m, 2H), 7.34-7.25 (m, 3H), 6.44 (d, J = 1.2 Hz, 1H), 6.39 (d,J = 1.5 Hz, 1H), 5.44 (s, 4H), 2.29 (s, 3H), 2.11 (s, 3H); ESI m/z 351[M + H]+. 98.6 178 (S)-4-amino-6- (3,5- dimethylisoxazol- 4-yl)-1-(1-phenylethyl)- 1H- benzo[d]imidazol- 2(3H)-one

P ¹H NMR (300 MHz, DMSO-d6) d 10.5 (s, 1H), 7.41-7.26 (m, 5H), 6.24 (d,J = 1.5 Hz, 1H), 5.97 (d, J = 1.2 Hz, 1H), 5.65 (q, J = 7.2 Hz, 1H),5.04 (s, 2H), 2.19 (s, 3H), 2.01 (s, 3H), 1.79 (d, J = 7.2 Hz, 3H); ESIMS m/z 349 [M + H]+. >99 179 (R)-4-amino-6- (3,5- dimethylisoxazol-4-yl)-1-(1- phenylethyl)- 1H- benzo[d]imidazol- 2(3H)-one

P ¹H NMR (300 MHz, DMSO-d6) d 10.5 (s, 1H), 7.41-7.26 (m, 5H), 6.24 (d,J = 1.5 Hz, 1H), 5.97 (d, J = 1.2 Hz, 1H), 5.65 (q, J = 7.2 Hz, 1H),5.04 (s, 2H), 2.19 (s, 3H), 2.01 (s, 3H), 1.79 (d, J = 7.2 Hz, 3H); ESIMS m/z 349 [M + H]+. >99 180 1-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-7-methyl-1H- imidazo[4,5- b]pyridin-2(3H)- one

No general procedure ¹H NMR (300 MHz, DMSO-d6) δ 11.89 (s, 1H), 7.74 (s,1H), 7.38-7.24 (m, 3H), 7.17-7.14 (m, 2H), 5.26 (s, 2H), 2.16 (s, 3H),2.01 (s, 3H), 1.99 (s, 3H); ESI m/z 335 [M + H]+. 94.3 1814-(1-benzyl-2,7- dimethyl-1H- imidazo[4,5- b]pyridin-6-yl)- 3,5-dimethylisoxazole

No general procedure ¹H NMR (300 MHz, CDCl3) δ 8.23 (s, 1H), 7.37-7.31(m, 3H), 6.95-6.92 (m, 2H), 5.58 (s, 2H), 2.64 (s, 3H), 2.23 (s, 3H),2.22 (s, 3H), 2.06 (s, 3H); ESI m/z 333 [M + H]+. 98.7 1824-(1-benzyl-6- (3,5- dimethylisoxazol- 4-yl)-2- methyl-1H-benzo[d]imidazol- 4- yl)morpholine

K ¹H NMR (300 MHz, CDCl3) δ 7.31-7.29 (m, 3H), 7.07-7.04 (m, 2H), 6.61(d, J = 1.2 Hz, 1H), 6.42 (d, J = 1.2 Hz, 1H), 5.30 (s, 2H), 4.00 (t, J= 4.5 Hz, 4H), 3.58 (t, J = 4.5 Hz, 4H), 2.58 (s, 3H), 2.32 (s, 3H),2.18 (s, 3H); ESI m/z 403 [M + H]+. >99 183 1-(1-benzyl-6- (3,5-dimethylisoxazol- 4-yl)-2- methyl-1H- benzo[d]imidazol- 4-yl)azetidin-2-one

K ¹H NMR (300 MHz, CDCl3) δ 7.75 (d, J = 1.2 Hz, 1H), 7.35- 7.29 (m,3H), 7.07- 7.05 (m, 2H), 6.72 (d, J = 1.5 Hz, 1H), 5.31 (s, 2H), 4.32(t, J = 4.5 Hz, 2H), 3.22 (t, J = 4.5 Hz, 2H), 2.60 (s, 3H), 2.33 (s,3H), 2.19 (s, 3H); ESI m/z 387 [M + H]+. >99 184 1-benzyl-2- methyl-6-(1,3,5- trimethyl-1H- pyrazol-4-yl)- 1H- benzo[d]imidazol- 4-amine

U ¹H NMR (300 MHz, DMSO-d6) δ 7.35- 7.16 (m, 5H), 6.40 (d, J = 1.2 Hz,1H), 6.23 (d, J = 1.2 Hz, 1H), 5.35 (s, 2H), 5.18 (s, 2H), 3.66 (s, 3H),2.50 (s, 3H), 2.13 (s, 3H), 2.04 (s, 3H); ESI MS m/z 346 [M + H]+. >99185 1-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-N- (pyridin-3-ylmethyl)-1H- imidazo[4,5- b]pyridin-2- amine

Q ¹H NMR (300 MHz, DMSO-d6) δ 8.60 (d, J = 1.6 Hz, 1H), 8.46 (dd, J =4.7 Hz, 1.6 Hz, 1H), 8.08-8.01 (m, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.77-7.72 (m, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.38-7.20 (m, 6H), >99 5.36 (s,2H), 4.69 (d, J = 5.8 Hz, 2H), 2.34 (s, 3H), 2.16 (s, 3H); ESI m/z 411[M + H]+. 186 4-(4-bromo-2- methyl-1- phenethyl-1H- benzo[d]imidazol-6-yl)-3,5- dimethylisoxazole

H ¹H NMR (500 MHz, DMSO-d6) δ 7.51 (s, 1H), 7.33 (s, 1H), 7.25-7.17 (m,3H), 7.10 (d, J = 7.0 Hz, 2H), 4.45 (t, J = 7.0 Hz, 2H), 3.03 (t, J =7.0 Hz, 2H), 2.40 (s, 3H), 2.29 (s, 3H), 2.23 (s, 3H); ESI m/z 410 [M +H]+. >99 187 4-(4-bromo-2- methyl-1-(3- phenylpropyl)- 1H-benzo[d]imidazol- 6-yl)-3,5- dimethylisoxazole

H ¹H NMR (500 MHz, DMSO-d6) δ 7.49 (d, J = 1.5 Hz, 1H), 7.35 (d, J = 1.5Hz, 1H), 7.26 (t, J = 7.5 Hz, 2H), 7.20 (d, J = 7.0 Hz, 2H), 7.17 (t, J= 7.0 Hz, 1H), 4.25 (t, J = 7.5 Hz, 2H), 2.65 (t, J = 7.5 Hz, 2H), 2.55(s, 3H), 2.41 (s, 3H), 2.23 (s, 3H), 2.06-2.00 (m, 2H); 98.6 ESI m/z 424[M + H]+. 188 4-(7-bromo-2- methyl-1-(3- phenylpropyl)- 1H-benzo[d]imidazol- 5-yl)-3,5- dimethylisoxazole

H ¹H NMR (500 MHz, DMSO-d6) δ 7.53 (d, J = 1.0 Hz, 1H), 7.34 (d, J = 1.5Hz, 1H), 7.32-7.23 (m, 4H), 7.20 (t, J = 7.0 Hz, 1H), 4.43 (t, J = 8.0Hz, 2H), 2.76 (t, J = 8.0 Hz, 2H), 2.53 (s, 3H), 2.39 (s, 3H), 2.21 (s,3H), 2.11- 2.04 (m, 2H); ESI m/z 424 [M + H]+. 99.0 189 4-(4-bromo-2-methyl-1-(2- phenoxyethyl)- 1H- benzo[d]imidazol- 6-yl)-3,5-dimethylisoxazole

H ¹H NMR (500 MHz, DMSO-d6) δ 7.63 (d, J = 1.0 Hz, 1H), 7.36 (d, J = 1.5Hz, 1H), 7.24 (td, J = 7.0, 2.0 Hz, 2H), 6.90 (t, J = 7.0 Hz, 1H), 6.84(d, J = 8.0 Hz, 2H), 4.66 (t, J = 5.0 Hz, 2H), 4.30 (t, J = 5.0 Hz, 2H),2.67 (s, 3H), 2.41 (s, 3H), 2.24 (s, 3H); ESI m/z 426 >99 [M + H]+. 1904-(7-bromo-2- methyl-1-(2- phenoxyethyl)- 1H- benzo[d]imidazol-5-yl)-3,5- dimethylisoxazole

H ¹H NMR (500 MHz, DMSO-d6) δ 7.55 (d, J = 1.5 Hz, 1H), 7.39 (d, J = 1.0Hz, 1H), 7.26 (t, J = 8.0 Hz, 2H), 6.94-6.89 (m, 3H), 4.89 (t, J = 5.0Hz, 2H), 4.40 (t, J = 5.0 Hz, 2H), 2.67 (s, 3H), 2.39 (s, 3H), 2.21 (s,3H); ESI m/z 426 [M + H]+. >99 191 4-(1- (cyclohexylmethyl)- 2-methyl-1H-imidazo[4,5- b]pyridin-6-yl)- 3,5- dimethylisoxazole

No general procedure ¹H NMR (500 MHz, CD3OD) δ 8.30 (d, J = 1.5 Hz, 1H),7.96 (d, J = 2.0 Hz, 1H), 4.14 (d, J = 7.5 Hz, 2H), 2.69 (s, 3H), 2.44(s, 3H), 2.28 (s, 3H), 1.95-1.82 (m, 1H), 1.76-1.50 (m, >99 5H),1.29-1.07 (m, 5H). ESI m/z 325 [M + H]+. 192 4-(1- (cyclopentylmethyl)-2-methyl- 1H-imidazo[4,5- b]pyridin-6-yl)- 3,5- dimethylisoxazole

No general procedure ¹H NMR (500 MHz, CD3OD) δ 8.30 (d, J = 2.0 Hz, 1H),7.98 (d, J = 2.0 Hz, 1H), 4.26 (d, J = 8.0 Hz, 2H), 2.71 (s, 3H),2.49-2.38 (m, 1H), 2.44 (s, 3H), 2.28 (s, 3H), 1.80-1.68 (m, 98.5 4H),1.66-1.57 (m, 2H), 1.40-1.27 (m, 2H). ESI m/z 311 [M + H]+. HPLC 98.5%.193 4-(1- (cyclobutylmethyl)- 2-methyl- 1H-imidazo[4,5- b]pyridin-6-yl)-3,5- dimethylisoxazole

No general procedure ¹H NMR (500 MHz, CD3OD) δ 8.30 (d, J = 1.5 Hz, 1H),8.00 (d, J = 1.5 Hz, 1H), 4.33 (d, J = 7.0 Hz, 2H), 2.92-2.80 (m, 1H),2.70 (s, 3H), 2.45 (s, 3H), 2.28 (s, 97.9 3H), 2.10-1.98 (m, 2H),1.96-1.81 (m, 4H). ESI m/z 297 [M + H]+. 194 1-benzyl-6-(3,5-dimethylisoxazol- 4-yl)-N- (pyridin-2- ylmethyl)-1H- imidazo[4,5-b]pyridin-2- amine

Q ¹H NMR (300 MHz, DMSO-d6) δ 8.56- 8.51 (m, 1H), 8.11 (t, J = 6.2 Hz,1H), 7.95 (d, J = 2.0 Hz, 1H), 7.72 (td, J = 7.7 Hz, 1.8 Hz, 1H), 7.47(d, J = 2.0 Hz, 1H), 7.38-7.25 (m, 7H), 5.40 (s, 2H), 4.75 (d, >99 J =5.9 Hz, 2H), 2.34 (s, 3H), 2.16 (s, 3H); ESI m/z 411 [M + H]+. 1954-(1-benzyl-2- (pyrrolidin-1- yl)-1H- imidazo[4,5- b]pyridin-6-yl)- 3,5-dimethylisoxazole

Q ¹H NMR (300 MHz, DMSO-d6) δ 8.04 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 2.0Hz, 1H), 7.37-7.22 (m, 3H), 7.16-7.09 (m, 2H), 5.51 (s, 2H), 3.61 (m,4H), 2.35 (s, 3H), 2.17 (s, 3H), 1.91- >99 1.86 (m, 4H); ESI m/z 374[M + H]+. 196 2-((1-benzyl-6- (3,5- dimethylisoxazol- 4-yl)-1H-imidazo[4,5- b]pyridin-2- yl)amino)ethanol

Q ¹H NMR (300 MHz, DMSO-d6) δ 7.95 (d, J = 2.0 Hz, 1H), 7.48 (t, J = 5.5Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.36-7.22 (m, 5H), 5.32 (s, 2H), 4.87(t, J = 5.4 Hz, 1H), 3.66-3.60 (m, 2H), 3.54-3.48 (m, 2H), 2.33 (s,3H), >99 2.14 (s, 3H); ESI m/z 364 [M + H]+. 197 1-(1-benzyl-6- (3,5-dimethylisoxazol- 4-yl)-2- methyl-1H- benzo[d]imidazol- 4-yl)azetidin-3-ol

K ¹H NMR (300 MHz, CDCl3) δ 7.36-7.24 (m, 3H), 7.18-7.15 (m, 2H), 6.73(d, J = 1.5 Hz, 1H), 5.95 (d, J = 1.5 Hz, 1H), 5.54 (d, J = 6.6 Hz, 1H),5.40 (s, 2H), 4.58- 4.53 (m, 1H), 4.37 (dd, J = 8.7, 6.3 Hz, 2H), 3.78(dd, J = 8.7, 5.4 Hz, 2H), 2.50 (s, 3H), 2.33 (s, 3H), 2.16 (s, 3H); ESIm/z 389 [M + H]+. 94.1 198 1-benzyl-3- methyl-6-(1- methyl-1H-pyrazol-5-yl)-4- nitro-1H- benzo[d]imidazol- 2(3H)-one

No general procedure ¹H NMR (300 MHz, CDCl3) δ 7.66 (d, J = 1.5 Hz, 1H),7.50 (d, J = 1.8 Hz, 1H), 7.36- 7.30 (m, 5H), 7.02 (d, J = 1.5 Hz, 1H),6.27 (d, J = 1.2 Hz, 1H), 5.16 (s, 2H), 3.69 (s, 3H), 3.65 (s, 3H); ESIm/z 364 [M + H]+. >99 199 4-amino-1- benzyl-3- methyl-6-(1- methyl-1H-pyrazol-5-yl)- 1H- benzo[d]imidazol- 2(3H)-one

No general procedure ¹H NMR (300 MHz, DMSO-d6) δ 7.39 (d, J = 1.8 Hz,1H), 7.35- 7.24 (m, 5H), 6.56 (d, J = 1.5 Hz, 1H), 6.54 (d, J = 1.5 Hz,1H), 6.20 (d, J = 1.8 Hz, 1H), 5.15 (s, 2H), 5.01 (s, 2H), 3.72 (s, 3H),3.63 (s, 3H); ESI m/z 334 [M + H]+. >99 200 (4-bromo-6- (3,5-dimethylisoxazol- 4-yl)-2- methyl-1H- benzo[d]imidazol- 1- yl)(phenyl)methanone

H ¹H NMR (500 MHz, DMSO-d6) δ 7.83 (dd, J = 8.0, 1.5 Hz, 2H), 7.78 (t, J= 7.5 Hz, 1H), 7.62 (t, J = 7.5 Hz, 2H), 7.53 (d, J = 1.5 Hz, 1H), 6.63(d, J = 1.5 Hz, 1H), 2.64 (s, 3H), 2.22 (s, 3H), 2.03 (s, 3H); ESI m/z410 [M + H]+. 96.1 201 1-benzyl-2- methyl-6-(5- methylisoxazol-4-yl)-1H- benzo[d]imidazol- 4-amine

U ¹H NMR (300 MHz, DMSO-d6) δ 8.69 (d, J = 0.6 Hz, 1H), 7.36- 7.26 (m,3H), 7.15 (d, J = 6.9 Hz, 2H), 6.78 (d, J = 1.5 Hz, 1H), 6.47 (d, J =1.5 Hz, 1H), 5.40 (s, 2H), 5.33 (s, 2H), 2.50 (s, 3H), 2.47 (s, 3H); ESIm/z 319 [M + H]+. 99.0 202 1- (cyclopentylmethyl)- 6-(3,5-dimethylisoxazol- 4-yl)-1H- imidazo[4,5- b]pyridin-2(3H)- one

No general procedure ¹H NMR (500 MHz, CD3OD) δ 7.90 (d, J = 1.5 Hz, 1H),7.47 (d, J = 2.0 Hz, 1H), 3.86 (d, J = 7.5 Hz, 2H), 2.52-2.38 (m, 1H),2.41 (s, 3H), 2.25 (s, 3H), 1.78- 1.68 (m, 4H), 1.60- >99 1.52 (m, 2H),1.41- 1.30 (m, 2H). ESI m/z 313 [M + H]+. 203 1- (cyclobutylmethyl)-6-(3,5- dimethylisoxazol- 4-yl)-1H- imidazo[4,5- b]pyridin-2(3H)- one

No general procedure ¹H NMR (500 MHz, CD3OD) δ 7.89 (d, J = 1.5 Hz, 1H),7.46 (d, J = 2.0 Hz, 1H), 3.94 (d, J = 7.0 Hz, 2H), 2.86-2.77 (m, 1H),2.41 (s, 3H), 2.25 (s, 3H), 2.08- 1.98 (m, 2H), 1.94- >99 1.80 (m, 4H).ESI m/z 299 [M + H]+. 204 N-(1-benzyl-3- methyl-6-(1- methyl-1H-pyrazol-5-yl)-2- oxo-2,3- dihydro-1H- benzo[d]imidazol- 4- yl)acetamide

P ¹H NMR (300 MHz, DMSO-d6) δ 9.81 (s, 1H), 7.43 (d, J = 1.8 Hz, 1H),7.40-7.26 (m, 5H), 7.20 (d, J = 1.5 Hz, 1H), 6.92 (d, J = 1.5 Hz, 1H),6.29 (d, J = 1.8 Hz, 1H), 5.10 (s, 2H), 3.75 (s, 3H), 3.47 (s, 3H), 2.08(s, 3H); ESI m/z 376 [M + H]+. >99 205 1-benzyl-6-(3,5-dimethylisoxazol- 4-yl)-N-(4- methoxybenzyl)- 1H- imidazo[4,5-b]pyridin-2- amine

Q ¹H NMR (300 MHz, DMSO-d6) δ 7.95 (d, J = 2.0 Hz, 1H), 7.94- 7.88 (m,1H), 7.43 (d, J = 2.0 Hz, 1H), 7.35-7.22 (m, 7H), 6.89-6.86 (m, 2H),5.35 (s, 2H), 4.60 (d, J = 5.7 Hz, 2H), 3.72 (s, 3H), 2.34 (s, 3H), 2.15(s, 3H); ESI m/z >99 440 [M + H]+. 206 1-benzyl-2- methyl-6-(1-methyl-1H- 1,2,3-triazol-5- yl)-1H- imidazo[4,5- b]pyridine

No general procedure ¹H NMR (500 MHz, DMSO-d6) δ 8.54 (d, J = 2.5 Hz,1H), 8.27 (d, J = 2.0 Hz, 1H), 7.96 (s, 1H), 7.35 (t, J = 7.0 Hz, 2H),7.29 (t, J = 7.0 Hz, 1H), 7.21 (d, J = 7.0 Hz, 2H), 5.58 (s, 2H), 98.64.07 (s, 3H), 2.60 (s, 3H); ESI m/z 305 [M + H]+. 207 4-((1-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-1H- imidazo[4,5- b]pyridin-2- yl)amino)cyclohexanol

Q ¹H NMR (500 MHz, DMSO-d6) δ 7.94 (d, J = 2.0 Hz, 1H), 7.35- 7.30 (m,3H), 7.27- 7.21 (m, 3H), 7.08 (d, J = 8.0 Hz, 1H), 5.32 (s, 2H), 4.57(d, J = 4.0 Hz, 1H), 3.83- 3.75 (m, 1H), 3.47- 3.40 (m, 1H), 2.32 (s,3H), 2.14 (s, 3H), 2.01 (br.d, 11.0 Hz, 2H), 1.88 (br.d, 11.5 Hz, 2H),1.44-1.35 >99 (m, 2H), 1.34-1.26 (m, 2H); ESI m/z 418 [M + H]+. 2084-(1- (cyclopentylmethyl)- 6-(3,5- dimethylisoxazol- 4-yl)-1H-imidazo[4,5- b]pyridin-2- yl)morpholine

No general procedure ¹H NMR (500 MHz, CD3OD) δ 8.17 (d, J = 1.5 Hz, 1H),7.81 (d, J = 2.0 Hz, 1H), 4.14 (d, J = 7.5 Hz, 2H), 3.87 (t, J = 5.0 Hz,4H), 3.41 (t, J = 5.0 Hz, 4H), 2.58- 2.49 (m, 1H), 2.43 98.5 (s, 3H),2.27 (s, 3H), 1.75-1.66 (m, 2H), 1.62-1.50 (m, 4H), 1.30-1.19 (m, 2H).ESI m/z 382 [M + H]+. 209 4-(2-(azetidin-1- yl)-1- (cyclopentylmethyl)-1H- imidazo[4,5- b]pyridin-6-yl)- 3,5- dimethylisoxazole

No general procedure ¹H NMR (500 MHz, CD3OD) δ 8.00 (d, J = 1.5 Hz, 1H),7.59 (d, J = 1.5 Hz, 1H), 4.42-4.37 (m, 4H), 4.01 (d, J = 8.0 Hz, 2H),2.57-2.44 (m, 2H), 2.50-2.41 (m, 1H), 2.41 (s, 3H), >99 2.25 (s, 3H),1.76- 1.51 (m, 6H), 1.32- 1.22 (m, 2H). ESI m/z 352 [M + H]+. 210 4-(1-(cyclobutylmethyl)- 6-(3,5- dimethylisoxazol- 4-yl)-1H- imidazo[4,5-b]pyridin-2- yl)morpholine

No general procedure ¹H NMR (500 MHz, CD3OD) δ 8.16 (d, J = 1.5 Hz, 1H),7.80 (d, J = 2.0 Hz, 1H), 4.24 (d, J = 7.0 Hz, 2H), 3.88 (t, J = 5.0 Hz,4H), 3.41 (t, J = 5.0 Hz, 4H), 2.93- 2.82 (m, 1H), 2.43 >99 (s, 3H),2.27 (s, 3H), 1.98-1.91 (m, 2H), 1.90-1.76 (m, 4H). ESI m/z 368 [M +H]+. 211 4-(2-(azetidin-1- yl)-1- (cyclobutylmethyl)- 1H- imidazo[4,5-b]pyridin-6-yl)- 3,5- dimethylisoxazole

No general procedure ¹H NMR (500 MHz, CD3OD) δ 7.99 (d, J = 2.0 Hz, 1H),7.61 (d, J = 2.0 Hz, 1H), 4.38 (m, 4H), 4.10 (d, J = 7.0 Hz, 2H),2.88-2.79 (m, 1H), 2.57-2.48 (m, 2H), 2.41 (s, 3H), 2.25 (s, >99 3H),2.04-1.95 (m, 2H), 1.95-1.78 (m, 4H). ESI m/z 338 [M + H]+. 212N1-(1-benzyl-6- (3,5- dimethylisoxazol- 4-yl)-1H- imidazo[4,5-b]pyridin-2-yl)- N2,N2- dimethylethane- 1,2-diamine

Q ¹H NMR (500 MHz, CD3OD) δ 7.95 (d, J = 1.9 Hz, 1H), 7.34 (d, J = 7.6Hz, 2H), 7.31-7.26 (m, 2H), 7.22 (d, J = 7.1 Hz, 2H), 5.31 (s, 2H), 3.69(t, J = 6.0 Hz, 2H), 2.71 (bs, 2H), >99 2.35 (s, 6H), 2.32 (s, 3H), 2.14(s, 3H); ESI m/z 391 [M + H]+. 213 4-(1-benzyl-2- (piperazin-1-yl)-1H-imidazo[4,5- b]pyridin-6-yl)- 3,5- dimethylisoxazole

Q ¹H NMR (300 MHz, CDCl3) δ 8.24 (d, J = 1.8 Hz, 1H), 7.37- 7.33 (m,3H), 7.18- 7.15 (m, 2H), 7.00 (d, J = 2.0 Hz, 1H), 5.23 (s, 2H), 3.51-3.48 (m, 4H), 3.14- 3.11 (m, 4H), 2.30 97.1 (s, 3H), 2.12 (s, 3H), 2.08(br. s, 1H); ESI m/z 389 [M + H]+. 214 1-benzyl-N- cyclopentyl-6- (3,5-dimethylisoxazol- 4-yl)-1H- imidazo[4,5- b]pyridin-2- amine

Q ¹H NMR (500 MHz, CD3OD) δ 7.93 (d, J = 1.9 Hz, 1H), 7.34 (t, J = 7.0Hz, 2H), 7.28 (t, J = 7.3 Hz, 1H), 7.23 (d, J = 1.9 Hz, 1H), 7.18 (d, J= 7.0 Hz, 2H), 5.36 (s, 2H), 4.39 (pentet, J = 6.5 Hz, 1H), 2.31 (s,3H), 2.13 (s, 3H), 2.15-2.00 (m, 2H), >99 1.95-1.30 (m, 6H); ESI m/z 388[M + H]+. 215 1-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-N-(2-morpholinoethyl)- 1H- imidazo[4,5- b]pyridin-2- amine

Q ¹H NMR (500 MHz, CD3OD) δ 7.95 (d, J = 1.9 Hz, 1H), 7.38- 7.32 (m,3H), 7.29 (t, J = 7.2 Hz, 1H), 7.23 (d, J = 7.0 Hz, 2H), 5.32 (s, 2H),3.68 (t, J = 6.3 Hz, 2H), 3.63 (t, J = 4.6 >99 Hz, 4H), 2.66 (t, J = 6.3Hz, 2H), 2.50 (t, J = 4.2 Hz, 4H), 2.33 (s, 3H), 2.15 (s, 3H); ESI m/z433 [M + H]+. 216 1-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-1H-imidazo[4,5- b]pyridin-2- amine

Q ¹H NMR (500 MHz, DMSO-d6) δ 7.93 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 2.0Hz, 1H), 7.33 (t, J = 7.0 Hz, 2H), 7.28-7.24 (m, 3H), 7.16 (s, 2H), 5.30(s, 2H), 2.33 (s, 3H), 2.15 (s, 3H); ESI 98.6 m/z 320 [M + H]+. 2173-(((1-benzyl-6- (3,5- dimethylisoxazol- 4-yl)-1H- imidazo[4,5-b]pyridin-2- yl)amino)methyl) benzonitrile

Q ¹H NMR (500 MHz, DMSO-d6) δ 8.03 (t, J = 6.0 Hz, 1H), 7.97 (d, J = 1.5Hz, 1H), 7.74 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.69 (d, J = 8.0 Hz,1H), 7.54 (t, J = 8.0 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.34 (td, J =7.0, 1.5 Hz, 2H), 7.28 (tt, J = 7.5, 1.5 Hz, 1H), 7.24 (d, J = 7.0 Hz,2H), 5.38 (s, >99 2H), 4.72 (d, J = 6.0 Hz, 2H), 2.34 (s, 3H), 2.16 (s,3H); ESI m/z 435 [M + H]+. 218 (R)-6-(3,5- dimethylisoxazol- 4-yl)-1-(1-phenylethyl)- 1H-imidazo[4,5- b]pyridin-2(3H)- one

No general procedure ¹H NMR (500 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.87 (d,J = 2.0 Hz, 1H), 7.44 (d, J = 7.5 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H),7.29 (t, J = 7.5 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H), 5.72 (q, J = 99.07.5 Hz, 1H), 2.26 (s, 3H), 2.06 (s, 3H), 1.84 (d, J = 7.5 Hz, 3H); ESIm/z 335 [M + H]+; HPLC (Chiralcel OD, 4.6 mm × 250 mm, 10% EtOH inheptane, 1 mL/min) >99%, tR = 9.4 min. 219 (S)-6-(3,5- dimethylisoxazol-4-yl)-1-(1- phenylethyl)- 1H-imidazo[4,5- b]pyridin-2(3H)- one

No general procedure ¹H NMR (500 MHz, DMSO-d6) δ 11.78 (s, 1H), 7.87 (d,J = 1.5 Hz, 1H), 7.44 (d, J = 7.5 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H),7.29 (t, J = 7.5 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 5.72 (q, J = >99 7.5Hz, 1H), 2.26 (s, 3H), 2.06 (s, 3H), 1.84 (d, J = 7.5 Hz, 3H); ESI m/z335 [M + H]+; HPLC (Chiralcel OD, 4.6 mm × 250 mm, 10% EtOH in heptane,1 mL/min) >99%, tR = 10.9 min. 220 4-(1-benzyl-2- (tetrahydro-2H-pyran-4-yl)-1H- imidazo[4,5- b]pyridin-6-yl)- 3,5- dimethylisoxazole

No general procedure ¹H NMR (300 MHz, CDCl3) δ 8.41 (d, J = 1.8 Hz, 1H),7.38- 7.32 (m, 3H), 7.24 (d, J = 2.1 Hz, 1H), 7.08-7.05 (m, 2H), 5.42(s, 2H), 4.12 (dd, J = 11.7, 1.8 Hz, 2H), 3.52 (td, J = 95.8 11.7, 1.8Hz, 2H), 3.20-3.12 (m, 1H), 2.36-2.23 (m, 5H), 2.14 (s, 3H), 1.83- 1.78(m, 2H); ESI m/z 389 [M + H]+. 221 1-benzyl-6-(3,5- dimethylisoxazol-4-yl)-N- methyl-1H- imidazo[4,5- b]pyridine-2- carboxamide

No general procedure ¹H NMR (300 MHz, DMSO-d6) δ 8.31 (q, J = 4.5 Hz,1H), 8.27 (d, J = 1.8 Hz, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.36-7.24 (m,5H), 5.54 (s, 2H), 3.00 (d, J = 4.8 Hz, 3H), 2.21 (s, 3H), 2.00 (s, 3H);ESI m/z >99 362 [M + H]+. 222 1- (cyclopentylmethyl)- 6-(3,5-dimethylisoxazol- 4-yl)-N- (tetrahydro-2H- pyran-4-yl)-1H- imidazo[4,5-b]pyridin-2- amine

No general procedure ¹H NMR (500 MHz, CD3OD) δ 7.94 (d, J = 1.5 Hz, 1H),7.50 (d, J = 2.0 Hz, 1H), 4.17-4.05 (m, 1H), 4.05 (d, J = 8.0 Hz, 2H),4.02-3.97 (m, 2H), 3.57 (t, J = 11.75 Hz, 2H), 2.44- 2.36 (m, 1H), 2.41(s, 3H), 2.25 (s, 3H), 2.08-2.00 (m, 2H), 98.0 1.78-1.64 (m, 6H),1.62-1.54 (m, 2H), 1.38-1.25 (m, 2H). ESI m/z 396 [M + H]+. 223 1-(cyclobutylmethyl)- 6-(3,5- dimethylisoxazol- 4-yl)-N- (tetrahydro-2H-pyran-4-yl)-1H- imidazo[4,5- b]pyridin-2- amine

No general procedure ¹H NMR (500 MHz, CD3OD) δ 7.93 (d, J = 2.0 Hz, 1H),7.52 (d, J = 2.0 Hz, 1H), 4.17-4.05 (m, 1H), 4.10 (d, J = 7.5 Hz, 2H),4.03-3.97 (m, 2H), 3.56 (t, J = 11.75 Hz, 2H), 2.86- 2.78 (m, 1H), 2.41(s, 3H), 2.25 (s, 3H), 2.08-1.92 (m, 8H), 96.4 1.75-1.64 (m, 2H). ESIm/z 382 [M + H]+. 224 N1-(1-benzyl-6- (3,5- dimethylisoxazol- 4-yl)-1H-imidazo[4,5- b]pyridin-2- yl)cyclohexane- 1,4-diamine

Q ¹H NMR (500 MHz, CD3OD) δ 7.95 (d, J = 2.0 Hz, 1H), 7.38- 7.32 (m,2H), 7.31- 7.28 (m, 2H), 7.21- 7.19 (m, 2H), 5.37 (s, 2H), 4.10-4.00 (m,1H), 3.02-2.97 (m, 1H), 2.32 (s, 3H), 2.14 (s, 3H), 1.93- 1.71 (m, 6H),1.60- 1.49 (m, 2H); ESI m/z 417 [M + H]+. 95.7 225 1-benzyl-N-(cyclohexylmethyl)- 6-(3,5- dimethylisoxazol- 4-yl)-1H- imidazo[4,5-b]pyridin-2- amine

Q ¹H NMR (500 MHz, CD3OD) δ 7.95 (d, J = 2.0 Hz, 1H), 7.38- 7.22 (m,4H), 7.21- 7.18 (m, 2H), 5.32 (s, 2H), 3.41-3.32 (m, 2H), 2.33 (s, 3H),2.15 (s, 3H), 1.79- 1.60 (m, 6H), 1.30- 1.10 (m, 3H), 0.99- 0.89 (m,2H); ESI >99 m/z 416 [M + H]+. 226 1-benzyl-6-(3,5- dimethylisoxazol-4-yl)-N-(3- methoxypropyl)- 1H- imidazo[4,5- b]pyridin-2- amine

Q ¹H NMR (500 MHz, CD3OD) δ 7.94 (d, J = 2.0 Hz, 1H), 7.38- 7.22 (m,4H), 7.21- 7.18 (m, 2H), 5.30 (s, 2H), 3.60 (t, J = 7.0 Hz, 2H), 3.45(t, J = 6.0 Hz, 2H), 3.28 (s, 3H), 2.33 (s, 3H), 2.15 (s, 3H), 1.94(quin, J = 6.5 Hz, 2H); ESI m/z 392 [M + >99 H]+. 227 1-benzyl-6-(3,5-dimethylisoxazol- 4-yl)-N- (oxetan-3-yl)- 1H-imidazo[4,5- b]pyridin-2-amine

Q ¹H NMR (500 MHz, CD3OD) δ 7.97 (d, J = 2.0 Hz, 1H), 7.38- 7.24 (m,4H), 7.21- 7.18 (m, 2H), 5.39 (s, 2H), 5.24-5.17 (m, 1H), 5.03 (t, J =7.0 Hz, 2H), 4.71 (t, J = 7.0 Hz, 2H), 2.30 (s, 3H), 2.12 (s, 3H); ESIm/z 376 [M + H]+. >99 228 6-(3,5- dimethylisoxazol- 4-yl)-1-(4-fluorobenzyl)- 1H-imidazo[4,5- b]pyridin-2(3H)- one

R ¹H NMR (300 MHz, DMSO-d6) δ 11.82 (s, 1H), 7.91 (d, J = 1.8 Hz, 1H),7.48 (d, J = 1.8 Hz, 1H), 7.46- 7.43 (m, 2H), 7.20- 7.14 (m, 2H), 5.03(s, 2H), 2.36 (s, 3H), 2.17 (s, 3H); ESI m/z >99 339 [M + H]+. 2291-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-N- (pyrazin-2- ylmethyl)-1H-imidazo[4,5- b]pyridin-2- amine

Q ¹H NMR (500 MHz, DMSO-d6) δ 9.13 (d, J = 1.5 Hz, 1H), 8.70 (d, J =5.5, 1H), 8.16 (t, J = 6.0 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.49 (d, J= 2.0 Hz, 1H), 7.39-7.27 (m, 6H), 5.42 (s, 2H), 4.74 (d, J = 6.0 Hz,2H), 2.33 (s, 3H), >99 2.15 (s, 3H); ESI m/z 412 [M + H]+. 2301-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-N- ((tetrahydro- 2H-pyran-4-yl)methyl)-1H- imidazo[4,5- b]pyridin-2- amine

Q ¹H NMR (500 MHz, DMSO-d6) δ 7.95 (d, J = 2.0 Hz, 1H), 7.42- 7.39 (m,2H), 7.32 (t, J = 7.0 Hz, 2H), 7.27-7.21 (m, 3H), 5.32 (s, 2H), 3.84(dd, J = 11.0, 2.5 Hz, 2H), 3.34 (t, J = 6.5 Hz, 2H), 3.25 (td, J = >9911.0, 2.0 Hz, 2H), 2.33 (s, 3H), 2.15 (s, 3H), 1.97-1.90 (m, 1H), 1.57(d, J = 12.0 Hz, 2H), 1.20 (qd, J = 12.0, 4.0 Hz, 2H); ESI m/z 418 [M +H]+. 231 1-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-N-(2-(4-methylpiperazin- 1-yl)ethyl)- 1H-imidazo[4,5- b]pyridin-2- amine

Q ¹H NMR (500 MHz, CD3OD) δ 7.95 (d, J = 1.9 Hz, 1H), 7.38- 7.26 (m,4H), 7.22 (d, J = 7.1 Hz, 2H), 5.31 (s, 2H), 3.67 (t, J = 6.3 Hz, 2H),2.68 (t, J = 6.3 Hz, 2H), 2.80-2.20 (broad >99 peak, 8H), 2.33 (s, 3H),2.26 (s, 3H), 2.15 (s, 3H); ESI m/z 446 [M + H]+. 232 6-(3,5-dimethylisoxazol- 4-yl)-1-(4- fluorobenzyl)- N-methyl-1H- imidazo[4,5-b]pyridin-2- amine

Q ¹H NMR (300 MHz, DMSO-d6) δ 7.96 (d, J = 1.8 Hz, 1H), 7.46 (d, J = 1.8Hz, 1H), 7.37-7.28 (m, 3H), 7.20-7.14 (m, 2H), 5.27 (s, 2H), 2.99 (d, J= 4.5 Hz, 3H), 2.35 (s, 3H), 2.17 (s, 3H); >99 ESI m/z 352 [M + H]+. 2331-(4- chlorobenzyl)- 6-(3,5- dimethylisoxazol- 4-yl)-N- methyl-1H-imidazo[4,5- b]pyridin-2- amine

Q ¹H NMR (300 MHz, DMSO-d6) δ 7.97 (d, J = 2.1 Hz, 1H), 7.44 (d, J = 1.8Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.33 (q, J = 4.2 Hz, 1H), 7.25 (d, J= 8.7 Hz, 2H), 5.28 (s, 2H), 2.99 (d, J = 4.8 >99 Hz, 3H), 2.35 (s, 3H),2.17 (s, 3H); ESI m/z 368 [M + H]+. 234 1-benzyl-N- cyclohexyl-6- (3,5-dimethylisoxazol- 4-yl)-1H- imidazo[4,5- b]pyridin-2- amine

Q ¹H NMR (300 MHz, DMSO-d6) δ 7.94 (d, J = 2.1 Hz, 1H), 7.35- 7.30 (m,3H), 7.27- 7.22 (m, 3H), 7.10 (d, J = 7.5 Hz, 1H), 5.33 (s, 2H), 3.90-3.75 (m, 1H), 2.32 (s, 3H), 2.14 (s, 3H), 2.00 (d, J = 7.2 Hz, 2H),1.81-1.71 (m, 2H), 1.64 (d, J = 11.7 >99 Hz, 1H), 1.42-1.30 (m, 4H),1.23-1.14 (m, 1H); ESI m/z 402 [M + H]+. 235 1-benzyl-6-(3,5-dimethylisoxazol- 4-yl)-N-(1- methylpiperidin- 4-yl)-1H- imidazo[4,5-b]pyridin-2- amine

Q ¹H NMR (300 MHz, DMSO-d6) δ 7.95 (d, J = 1.8 Hz, 1H), 7.38 (d, J = 2.1Hz, 1H), 7.36-7.30 (m, 2H), 7.28-7.22 (m, 3H), 7.16 (d, J = 7.5 Hz, 1H),5.34 (s, 2H), 3.85-3.73 (m, 1H), 2.78 (d, J = 10.5 Hz, 2H), 2.33 (s,3H), 2.18 (s, 3H), 2.14 (s, 3H), 2.04-1.93 (m, 4H), 1.67-1.54 (m, 97.02H); ESI m/z 417 [M + H]+. 236 4-(1-benzyl-2- (pyridin-3- yloxy)-1H-imidazo[4,5- b]pyridin-6-yl)- 3,5- dimethylisoxazole

T ¹H NMR (300 MHz, DMSO-d6) δ 8.74 (d, J = 2.7 Hz, 1H), 8.57 (dd, J =4.5, 0.9 Hz, 1H), 8.27 (d, J = 1.8 Hz, 1H), 8.02-7.98 (m, 2H), 7.59 (dd,J = 8.4, 4.5 Hz, 1H), 7.47 (d, J = 6.9 Hz, 2H), 7.42-7.30 (m, 3H), 5.53(s, 2H), 2.40 (s, 3H), 2.22 (s, 98.0 3H); ESI m/z 398 [M + H]+. 2371-((1-benzyl-6- (3,5- dimethylisoxazol- 4-yl)-1H- imidazo[4,5-b]pyridin-2- yl)amino)-2- methylpropan- 2-ol

Q ¹H NMR (500 MHz, CD3OD) δ 7.94 (d, J = 2.0 Hz, 1H), 7.38- 7.28 (m,4H), 7.27- 7.21 (m, 2H), 5.35 (s, 2H), 3.55 (s, 2H), 2.33 (s, 3H), 2.15(s, 3H), 1.20 (s, 6H); ESI m/z 392 [M + H]+. >99 238 1-benzyl-6-(3,5-dimethylisoxazol- 4-yl)-N-(2- (pyrrolidin-1- yl)ethyl)-1H- imidazo[4,5-b]pyridin-2- amine

Q ¹H NMR (500 MHz, CD3OD) δ 7.94 (d, J = 2.0 Hz, 1H), 7.38- 7.28 (m,4H), 7.27- 7.21 (m, 2H), 5.31 (s, 2H), 3.70 (t, J = 6.5 Hz, 2H), 2.81(t, J = 6.5 Hz, 2H), 2.70- 2.55 (m, 4H), 2.32 (s, 3H), 2.14 (s, 3H),1.89-1.76 (m, 4H); ESI m/z 417 [M + H]+. 98.1 239 1-benzyl-6-(3,5-dimethylisoxazol- 4-yl)-N-(2- (piperidin-1- yl)ethyl)-1H- imidazo[4,5-b]pyridin-2- amine

Q ¹H NMR (500 MHz, CD3OD) δ 7.95 (d, J = 1.5 Hz, 1H), 7.38- 7.28 (m,4H), 7.27- 7.21 (m, 2H), 5.31 (s, 2H), 3.69 (t, J = 6.5 Hz, 2H), 2.66(t, J = 6.5 Hz, 2H), 2.60- 2.40 (m, 4H), 2.33 (s, 3H), 2.15 (s, 3H),1.66-1.57 (m, 4H), 1.52-1.42 (m, 2H); ESI m/z 431 [M + H]+. >99 240(R)-6-(3,5- dimethylisoxazol- 4-yl)-4-nitro- 1-(1- phenylethyl)- 1H-benzo[d]imidazol- 2(3H)-one

P ¹H NMR (300 MHz, DMSO-d6) δ 12.1 (s, 1H), 7.68 (d, J = 1.5 Hz, 1H),7.45-7.29 (m, 5H), 7.13 (d, J = 1.2 Hz, 1H), 5.79 (q, J = 7.2 Hz, 1H),2.25 (s, 3H), 2.04 (s, 3H), 1.88 (d, J = 7.2 Hz, 3H); ESI MS m/z 379[M + H]+. 98.1 241 4-(1-benzyl-7- methoxy-2- (trifluoromethyl)- 1H-benzo[d]imidazol- 6-yl)-3,5- dimethylisoxazole

No general procedure ¹H NMR (300 MHz, DMSO-d6) δ 7.72 (d, J = 8.4 Hz,1H), 7.36- 7.26 (m, 4H), 7.03- 7.00 (m, 2H), 5.81 (s, 2H), 3.13 (s, 3H),2.27 (s, 3H), 2.09 (s, 3H); ESI m/z 402 [M + H]+. 95.6 2421-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-N- (thiazol-2- ylmethyl)-1H-imidazo[4,5- b]pyridin-2- amine

Q ¹H NMR (500 MHz, CD₃OD) δ 7.98 (d, J = 1.9 Hz, 1H), 7.73 (d, J = 3.3Hz, 1H), 7.49 (d, J = 3.3 Hz, 1H), 7.38-7.22 (m, 6H), 5.37 (s, 2H), 5.07(s, 2H), 2.32 (s, 3H), 2.14 (s, 3H); ESI m/z 417 [M + H]+. >99 2431-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-1H- benzo[d]imidazole- 2-carboximidamide

No general procedure ¹H NMR (500 MHz, DMSO-d₆) δ 7.77 (d, J = 8.3 Hz,1H), 7.49 (s, 1H), 7.36 (s, 1H), 7.33-7.19 (m, 6H), 6.58 (s, 2H), 6.27(s, 2H), 2.32 (s, 3H), 2.15 (s, 3H); ESI m/z 346 [M + H]+. >99 2441-benzyl-6-(3,5- dimethylisoxazol- 4-yl)-1H- benzo[d]imidazole- 2-carboxamide

No general procedure ¹H NMR (500 MHz, DMSO-d₆) δ 8.38 (s, 1H), 7.92 (s,1H), 7.82 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 1.0 Hz, 1H), 7.33-7.28 (m,5H), 7.27-7.22 (m, 1H), 6.02 (s, 2H), 2.35 (s, 3H), 2.18 (s, 3H); ESIm/z 347 >99 [M + H]+. 245 1-benzyl-6-(3,5- dimethylisoxazol-4-yl)-N-((1- methylpiperidin- 4-yl)methyl)- 1H-imidazo[4,5- b]pyridin-2-amine

Q ¹H NMR (500 MHz, DMSO-d₆) δ 7.94 (d, J = 2.0 Hz, 1H), 7.34-7.37 (m,2H), 7.32 (t, J = 7.0 Hz, 2H), 7.27-7.21 (m, 3H), 5.31 (s, 2H), 3.32 (t,J = 6.0 Hz, 2H), 2.84-2.72 (m, 2H), 2.33 (s, 3H), >99 2.16 (br.s, 3H),2.15 (s, 3H), 1.98-1.71 (m, 2H), 1.69-1.61 (m, 3H), 1.23-1.15 (m, 2H);ESI m/z 431 [M + H]+. 246 1-(1-benzyl-6- (3,5- dimethylisoxazol-4-yl)-1H- imidazo[4,5- b]pyridin-2- yl)azetidin-3-ol

Q ¹H NMR (300 MHz, DMSO-d₆) δ 7.74 (s, 1H), 7.41 (d, J = 6.6 Hz, 2H),7.36-7.23 (m, 3H), 7.18 (s, 1H), 5.20 (d, J = 3.3 Hz, 1H), 5.04 (s, 2H),4.12 (d, J = 3.3 Hz, 1H), 3.89 (qd, J = >99 12.0, 3.3 Hz, 2H), 3.45 (qd,J = 14.4, 3.3 Hz, 2H), 2.33 (s, 3H), 2.14 (s, 3H); ESI m/z 376 [M + H]+.247 4-(1-benzyl-2- (pyridin-4- yloxy)-1H- imidazo[4,5- b]pyridin-6-yl)-3,5- dimethylisoxazole

T ¹H NMR (500 MHz, DMSO-d₆) δ 8.54 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 2.0Hz, 1H), 8.00 (dd, J = 6.0, 2.0 Hz, 2H), 7.32-7.27 (m, 3H), 7.12 (dd, J= 8.0, 1.0 Hz, 2H), 6.26 (dd, J = 6.0, 2.0 Hz, 2H), 5.57 (s, 2H), 2.41(s, 3H), 2.23 (s, 3H); ESI m/z 398 >99 [M + H]+. 248 1-benzyl-6-(3,5-dimethylisoxazol- 4-yl)-N- (pyridin-3-yl)- 1H- benzo[d]imidazol- 2-amine

No general procedure ESI m/z 396 [M + H]+. — 249 3-(1-benzyl-1H-benzo[d]imidazol- 6-yl)-4-ethyl- 1H-1,2,4- triazol-5(4H)- one

No general procedure ¹H NMR (300 MHz, DMSO-d₆) δ 11.85 (s, 1H), 8.59 (s,1H), 7.81-7.76 (m, 2H), 7.43 (dd, J = 8.1, 1.5 Hz, 1H), 7.35-7.28 (m,5H), 5.58 (s, 2H), 3.63 (q, J = 7.2, Hz 2H), 0.98 (t, J = 7.2 Hz, 3H);ESI m/z 320 — [M + H]+.

Example 1: Inhibition of Tetra-Acetylated Histone H4 Binding IndividualBET Bromodomains

Proteins were cloned and overexpressed with a N-terminal 6×His tag, thenpurified by nickel affinity followed by size exclusion chromatography.Briefly, E. coli BL21(DE3) cells were transformed with a recombinantexpression vector encoding N-terminally Nickel affinity taggedbromodomains from Brd2, Brd3, Brd4. Cell cultures were incubated at 37°C. with shaking to the appropriate density and induced overnight withIPTG. The supernatant of lysed cells was loaded onto Ni-IDA column forpurification. Eluted protein was pooled, concentrated and furtherpurified by size exclusion chromatography. Fractions representingmonomeric protein were pooled, concentrated, aliquoted, and frozen at−80° C. for use in subsequent experiments.

Binding of tetra-acetylated histone H4 and BET bromodomains wasconfirmed by a Time Resolved Fluorescence Resonance Energy Transfer(TR-FRET) method. N-terminally His-tagged bromodomains (200 nM) andbiotinylated tetra-acetylated histone H4 peptide (25-50 nM, Millipore)were incubated in the presence of Europium Cryptate-labeled streptavidin(Cisbio Cat. #610SAKLB) and XL665-labeled monoclonal anti-His antibody(Cisbio Cat. #61HISXLB) in a white 96 well microtiter plate (Greiner).For inhibition assays, serially diluted test compound was added to thesereactions in a 0.2% final concentration of DMSO. Final bufferconcentrations were 30 mM HEPES pH 7.4, 30 mM NaCl, 0.3 mM CHAPS, 20 mMphosphate pH 7.0, 320 mM KF, 0.08% BSA). After a 2-h incubation at roomtemperature, the fluorescence by FRET was measured at 665 and 620 nm bya SynergyH4 plate reader (Biotek). Illustrative results with the firstbromodomain of Brd4 are shown below. The binding inhibitory activity wasshown by a decrease in 665 nm fluorescence relative to 620 nm. IC₅₀values were determined from a dose response curve.

Compounds with an IC₅₀ value less than or equal to 0.3 μM were deemed tobe highly active (+++); compounds with an IC₅₀ value between 0.3 and 3μM were deemed to be very active (++); compounds with an IC₅₀ valuebetween 3 and 30 μM were deemed to be active (+).

TABLE 3 Inhibition of Tetra-acetylated Histone H4 Binding to Brd4bromodomain 1 (BRD4(1) as Measured by FRET FRET Example activityCompound BRD4(1) 1 ++ 2 +++ 3 ++ 4 ++ 5 +++ 6 ++ 7 +++ 8 +++ 9 + 10 +++11 +++ 12 +++ 13 +++ 14 +++ 15 +++ 16 +++ 17 +++ 18 +++ 19 +++ 20 +++ 21+++ 22 ++ 23 ++ 24 +++ 25 + 26 ++ 27 +++ 28 +++ 29 +++ 30 +++ 31 ++ 32Not active 33 +++ 34 +++ 35 +++ 36 +++ 37 ++ 38 +++ 39 +++ 40 ++ 41 +++42 ++ 43 +++ 44 ++ 45 +++ 46 ++ 47 + 48 +++ 49 + 50 +++ 51 +++ 52 ++ 53+++ 54 +++ 55 +++ 56 ++ 57 + 58 +++ 59 ++ 60 ++ 61 +++ 62 +++ 63 ++ 64+++ 65 +++ 66 +++ 67 +++ 68 +++ 69 +++ 70 +++ 71 +++ 72 ++ 73 ++ 74 ++75 +++ 76 ++ 77 +++ 78 +++ 79 Not active 80 ++ 81 ++ 82 ++ 83 +++ 84 +++85 +++ 86 +++ 87 +++ 88 +++ 89 +++ 90 +++ 91 +++ 92 +++ 93 +++ 94 +++ 95+++ 96 +++ 97 +++ 98 ++ 99 +++ 100 +++ 101 ++ 102 +++ 103 +++ 104 +++105 +++ 106 +++ 107 +++ 108 +++ 109 +++ 110 +++ 111 +++ 112 +++ 113 +++114 +++ 115 +++ 116 +++ 117 +++ 118 +++ 119 +++ 120 +++ 121 +++ 122 +++123 +++ 124 +++ 125 +++ 126 +++ 127 +++ 128 +++ 129 +++ 130 +++ 131 +++132 +++ 133 +++ 134 +++ 135 +++ 136 +++ 137 +++ 138 +++ 139 +++ 140 +++141 +++ 142 ++ 143 +++ 144 +++ 145 +++ 146 +++ 147 +++ 148 +++ 149 +++150 +++ 151 +++ 152 +++ 153 +++ 154 +++ 155 +++ 156 +++ 157 +++ 158 +++159 +++ 160 +++ 161 +++ 162 +++ 163 +++ 164 +++ 165 +++ 166 ++ 167 +++168 +++ 169 +++ 170 +++ 171 ++ 172 +++ 173 +++ 174 +++ 175 ++ 176 ++ 177++ 178 +++ 179 +++ 180 +++ 181 +++ 182 +++ 183 +++ 184 + 185 +++ 186 +++187 ++ 188 + 189 ++ 190 ++ 191 +++ 192 +++ 193 +++ 194 +++ 195 +++ 196+++ 197 +++ 198 +++ 199 +++ 200 ++ 201 +++ 202 +++ 203 +++ 204 ++ 205+++ 206 +++ 207 +++ 208 +++ 209 +++ 210 +++ 211 +++ 212 +++ 213 +++ 214+++ 215 +++ 216 +++ 217 +++ 218 +++ 219 ++ 220 +++ 221 +++ 222 +++ 223+++ 224 +++ 225 +++ 226 +++ 227 +++ 228 +++ 229 +++ 230 +++ 231 +++ 232+++ 233 +++ 234 +++ 235 +++ 236 +++ 237 +++ 238 +++ 239 +++ 240 +++ 241++ — — — — — —

Example 2: Inhibition of c-Myc Expression in Cancer Cell Lines

MV4-11 cells (CRL-9591) were plated at a density of 2.5×10⁴ cells perwell in 96 well U-bottom plates and treated with increasingconcentrations of test compound or DMSO (0.1%) in IMDM media containing10% FBS and penicillin/streptomycin, and incubated for 3 h at 37° C.Triplicate wells were used for each concentration. Cells were pelletedby centrifugation and harvested using the mRNA Catcher PLUS kitaccording to manufacturer's instructions. The eluted mRNA isolated wasthen used in a one-step quantitative real-time PCR reaction, usingcomponents of the RNA UltraSense™ One-Step Kit (Life Technologies)together with Applied Biosystems TaqMan® primer-probes for cMYC andCyclophilin. Real-time PCR plates were run on a Vla™7 real time PCRmachine (Applied Biosystems), data was analyzed, normalizing the Ctvalues for cMYC to an internal control, prior to determining the foldexpression of each sample, relative to the control.

Compounds with an IC₅₀ value less than or equal to 0.3 μM were deemed tobe highly active (+++); compounds with an IC₅₀ value between 0.3 and 3μM were deemed to be very active (++); compounds with an IC₅₀ valuebetween 3 and 30 μM were deemed to be active (+).

TABLE 4 Inhibition of c-myc Activity in Human AML MV4-11 cells Examplec-myc Compound activity 1 Not active 2 + 3 + 4 ++ 5 ++ 6 ++ 7 ++ 8 ++9 + 10 ++ 11 Not active 12 ++ 13 ++ 14 ++ 15 ++ 16 +++ 17 +++ 18 +++ 19+++ 20 Not active 22 ++ 23 Not active 24 + 26 + 27 ++ 28 ++ 29 ++ 30 ++31 Not active 33 ++ 34 ++ 35 ++ 36 ++ 37 + 38 + 39 ++ 40 Not active 41Not active 42 + 43 Not active 44 + 45 ++ 46 + 47 Not active 48 ++ 49 +50 + 51 ++ 52 + 53 Not active 54 ++ 55 +++ 56 Not active 58 ++ 60 + 61++ 62 ++ 63 + 64 +++ 65 ++ 66 ++ 67 +++ 68 ++ 69 ++ 70 Not active 71 ++72 + 73 + 74 + 75 ++ 76 ++ 77 ++ 78 + 79 Not active 80 Not active 81 +82 ++ 83 ++ 84 ++ 85 +++ 86 ++ 87 +++ 88 ++ 89 ++ 90 +++ 91 ++ 92 ++93 + 94 ++ 95 ++ 96 +++ 97 +++ 98 ++ 99 ++ 100 ++ 102 +++ 103 ++ 104 ++105 ++ 106 ++ 108 ++ 109 +++ 110 ++ 111 +++ 112 +++ 113 +++ 114 ++ 115+++ 116 +++ 117 +++ 118 ++ 119 +++ 120 ++ 121 +++ 122 ++ 123 +++ 124 ++125 +++ 126 +++ 127 +++ 128 ++ 129 +++ 130 ++ 131 ++ 132 ++ 133 +++ 134+++ 138 +++ 139 +++ 140 +++ 141 +++ 142 ++ 143 +++ 144 +++ 145 + 146 +++148 ++ 149 +++ 150 Not active 151 +++ 152 +++ 153 +++ 154 Not active155 + 156 ++ 157 +++ 158 ++ 159 +++ 160 ++ 161 Not active 163 ++ 165 ++167 +++ 168 ++ 169 +++ 170 +++ 171 ++ 172 +++ 173 +++ 174 ++ 176 ++ 177+++ 178 +++ 179 +++ 180 ++ 181 +++ 182 ++ 183 ++ 185 +++ 186 + 191 +++192 ++ 193 ++ 194 +++ 195 +++ 196 +++ 197 +++ 198 + 199 ++ 200 Notactive 201 ++ 202 ++ 203 + 205 ++ 206 Not active 208 +++ 209 ++ 210 ++211 ++ 212 ++ 213 ++ 214 +++ 215 +++ 216 ++ 217 +++ 218 ++ 219 ++ 220 +221 ++ 222 +++ 223 +++ — — — — — —

Example 3: Inhibition of Cell Proliferation in Cancer Cell Lines

MV4-11 cells: 96-well plates were seeded with 5×10⁴ cells per well ofexponentially growing human AML MV-4-11 (CRL-9591) cells and immediatelytreated with two-fold dilutions of test compounds, ranging from 30 μM to0.2 μM. Triplicate wells were used for each concentration, as well as amedia only and three DMSO control wells. The cells and compounds wereincubated at 37° C., 5% CO₂ for 72 h before adding 20 μL of theCellTiter Aqueous One Solution (Promega) to each well and incubating at37° C. 5% CO₂ for an additional 3-4 h. The absorbance was taken at 490nm in a spectrophotometer and the percentage of proliferation relativeto DMSO-treated cells was calculated after correction from the blankwell. IC₅₀ were calculated using the GraphPad Prism software.

Compounds with an IC₅₀ value less than or equal to 0.3 μM were deemed tobe highly active (+++); compounds with an IC₅₀ value between 0.3 and 3μM were deemed to be very active (++); compounds with an IC₅₀ valuebetween 3 and 30 μM were deemed to be active (+).

TABLE 5 Inhibition of Cell Proliferation in Human AML MV-4-11 cells CellExample Proliferation Compound activity 1 Not active 2 ++ 3 + 4 + 5 ++ 6++ 7 +++ 8 ++ 9 + 10 ++ 11 Not active 12 ++ 13 ++ 14 + 15 ++ 16 +++ 17++ 18 +++ 19 +++ 20 Not active 21 ++ 22 ++ 23 + 24 Not active 25 Notactive 26 ++ 27 ++ 28 ++ 29 ++ 30 ++ 31 + 33 + 34 ++ 35 ++ 36 ++ 37 Notactive 38 Not active 39 ++ 40 Not active 41 ++ 42 + 43 ++ 44 + 45 ++46 + 47 Not active 48 + 49 + 50 + 51 ++ 52 ++ 53 Not active 54 ++ 55 +++57 + 58 ++ 59 Not active 60 Not active 61 + 62 ++ 64 ++ 65 ++ 66 ++ 67++ 68 + 69 ++ 70 + 71 ++ 72 + 73 + 74 + 75 ++ 76 + 77 ++ 78 + 79 Notactive 80 Not active 81 + 82 + 83 ++ 84 ++ 86 + 87 +++ 88 ++ 89 ++ 90 ++91 + 92 ++ 93 + 94 ++ 95 ++ 96 +++ 97 +++ 98 ++ 99 ++ 100 ++ 102 ++ 103++ 104 ++ 105 ++ 106 ++ 107 ++ 108 ++ 109 +++ 110 ++ 111 +++ 112 ++ 113+++ 114 ++ 115 +++ 116 +++ 117 +++ 118 ++ 119 +++ 120 ++ 121 +++ 122 +++123 ++ 124 ++ 125 ++ 126 ++ 127 +++ 128 ++ 129 ++ 130 ++ 131 ++ 132 ++133 ++ 134 +++ 135 ++ 136 ++ 137 +++ 138 ++ 139 +++ 140 +++ 141 +++142 + 143 +++ 144 +++ 145 + 146 +++ 148 ++ 149 ++ 150 Not active 151 +++152 ++ 153 +++ 154 + 155 Not active 156 ++ 157 +++ 158 ++ 159 ++ 160 ++161 ++ 162 +++ 163 ++ 165 ++ 167 +++ 168 ++ 169 +++ 170 +++ 171 ++ 172++ 173 ++ 174 ++ 176 ++ 177 +++ 178 ++ 179 +++ 180 ++ 181 ++ 182 ++183 + 185 +++ 186 Not active 191 ++ 192 ++ 193 ++ 194 +++ 195 +++ 196 ++197 +++ 198 + 199 ++ 200 Not active 201 ++ 202 ++ 203 + 205 ++ 206 + 207+++ 208 ++ 209 +++ 210 ++ 211 +++ 212 ++ 213 ++ 214 +++ 215 ++ 216 +++217 ++ 218 + 219 ++ 220 ++ 221 ++ 222 +++ 223 ++

Example 4: Inhibition of hIL-6 mRNA Transcription

In this example, hIL-6 mRNA in tissue culture cells was quantitated tomeasure the transcriptional inhibition of hIL-6 when treated with acompound of the invention.

In this example, hIL-6 mRNA in tissue culture cells was quantitated tomeasure the transcriptional inhibition of hIL-6 when treated with acompound of the invention.

Human leukemic monocyte lymphoma U937 cells (CRL-1593.2) were plated ata density of 3.2×104 cells per well in a 96-well plate in 100 μLRPMI-1640 containing 10% FBS and penicillin/streptomycin, anddifferentiated into macrophages for 3 days in 60 ng/mL PMA(phorbol-13-myristate-12-acetate) at 37° C. in 5% CO2 prior to theaddition of compound. The cells were pretreated for 1 h with increasingconcentrations of test compound in 0.1% DMSO prior to stimulation with 1ug/mL lipopolysaccharide from Escherichia coli. Triplicate wells wereused for each concentration. The cells were incubated at 37° C. 5% CO2for 3 h before the cells were harvested. At time of harvest, media wasremoved and cells were rinsed in 200 μL PBS. Cells were harvested usingthe mRNA Catcher PLUS kit according to manufacturer's instructions. Theeluted mRNA was then used in a one-step quantitative real-time PCRreaction using components of the RNA UltraSense™ One-Step Kit (LifeTechnologies) together with Applied Biosystems TaqMan® primer-probes forhIL-6 and Cyclophilin. Real-time PCR plates were run on a Vla™7 realtime PCR machine (Applied Biosystems), data was analyzed, normalizingthe Ct values for hIL-6 to an internal control, prior to determining thefold expression of each sample, relative to the control.

Compounds with an IC₅₀ value less than or equal to 0.3 μM were deemed tobe highly active (+++); compounds with an IC₅₀ value between 0.3 and 3μM were deemed to be very active (++); compounds with an IC₅₀ valuebetween 3 and 30 μM were deemed to be active (+).

TABLE 6 Inhibition of hIL-6 mRNA Transcription Example IL-6 Compoundactivity 1 ++ 2 ++ 3 + 4 ++ 5 ++ 6 ++ 7 +++ 8 ++ 9 + 10 +++ 11 ++ 12 ++13 +++ 14 ++ 15 ++ 16 +++ 17 ++ 18 ++ 19 +++ 20 Not active 21 +++ 22 ++23 ++ 24 ++ 25 Not active 26 ++ 27 ++ 28 ++ 29 ++ 30 ++ 31 ++ 33 ++ 34++ 35 ++ 36 ++ 37 + 38 + 39 ++ 40 + 41 + 42 + 43 ++ 44 ++ 45 ++ 46 + 47Not active 48 ++ 49 + 50 ++ 51 ++ 52 ++ 53 ++ 54 ++ 55 +++ 56 + 58 ++ 59Not active 60 ++ 61 ++ 62 ++ 63 ++ 64 +++ 65 ++ 66 ++ 67 +++ 68 ++ 69 ++70 ++ 71 ++ 72 + 73 ++ 74 ++ 75 ++ 76 ++ 77 ++ 78 ++ 79 Not active 80Not active 81 ++ 82 ++ 83 ++ 84 ++ 85 ++ 86 ++ 87 +++ 88 +++ 89 ++ 91 ++92 ++ 93 ++ 94 ++ 95 ++ 96 +++ 97 +++ 98 ++ 99 ++ 100 ++ 102 +++ 103 ++105 ++ 106 ++ 108 +++ 109 +++ 111 +++ 112 ++ 113 +++ 114 ++ 115 +++ 116++ 117 +++ 118 ++ 119 +++ 121 ++ 122 ++ 123 +++ 127 +++ 129 +++ 131 ++132 +++ 133 +++ 135 +++ 136 ++ 137 +++ 140 +++ 141 +++ 143 +++ 144 +++146 +++ 148 +++ 149 +++ 150 ++ 151 +++ 152 +++ 153 +++ 154 + 155 ++ 156++ 157 +++ 158 ++ 162 +++ 164 +++ 207 +++ 208 +++ 209 +++ 211 +++ 214+++ 215 +++ 216 +++ 217 +++ 218 ++ 220 ++ 221 ++ 223 ++ — — — — — —

Example 5: Inhibition of IL-17 mRNA Transcription

In this example, hIL-17 mRNA in human peripheral blood mononuclear cellswas quantitated to measure the transcriptional inhibition of hIL-17 whentreated with a compound of the invention.

Human peripheral blood mononuclear cells were plated (2.0×10⁵ cells perwell) in a 96-well plate in 45 μL OpTimizer T Cell expansion mediacontaining 20 ng/ml IL-2 and penicillin/streptomycin. The cells weretreated with the test compound (45 μL at 2× concentration), and then thecells were incubated at 37° C. for 1 h before addition of 10× stock OKT3antibody at 10 μg/ml in media. Cells were incubated at 37° C. for 6 hbefore the cells were harvested. At time of harvest, cells werecentrifuged (800 rpm, 5 min). Spent media was removed and cell lysissolution (70 μL) was added to the cells in each well and incubated for5-10 min at room temperature, to allow for complete cell lysis anddetachment. mRNA was then prepared using the “mRNA Catcher PLUS plate”(Invitrogen), according to the protocol supplied. After the last wash,as much wash buffer as possible was aspirated without allowing the wellsto dry. Elution buffer (E3, 70 μL) was then added to each well. mRNA wasthen eluted by incubating the mRNA Catcher PLUS plate with ElutionBuffer for 5 min at 68° C. and then immediately placing the plate onice.

The eluted mRNA isolated was then used in a one-step quantitative RT-PCRreaction, using components of the Ultra Sense Kit together with AppliedBiosystems primer-probe mixes. Real-time PCR data was analyzed,normalizing the Ct values for hIL-17 to an internal control, prior todetermining the fold induction of each unknown sample, relative to thecontrol.

Compounds with an IC₅₀ value less than or equal to 0.3 μM were deemed tobe highly active (+++); compounds with an IC₅₀ value between 0.3 and 3μM were deemed to be very active (++); compounds with an IC₅₀ valuebetween 3 and 30 μM were deemed to be active (+).

TABLE 7 Inhibition of hIL-17 mRNA Transcription Example I1-17 Compoundactivity 5 ++ 7 +++ 8 ++ 10 +++ 13 ++ 16 ++ 18 ++ 19 +++ 30 ++ 45 ++ 51++ 53 + 55 +++ 64 +++ 105 ++ 106 ++ 112 +++ — — — — — —

Example 6: Inhibition of hVCAMmRNA Transcription

In this example, hVCAMmRNA in tissue culture cells is quantitated tomeasure the transcriptional inhibition of hVCAM when treated with acompound of the present disclosure.

Human umbilical vein endothelial cells (HUVECs) are plated in a 96-wellplate (4.0×10³ cells/well) in 100 μL EGM media and incubated for 24 hprior to the addition of the compound of interest. The cells arepretreated for 1 h with the test compound prior to stimulation withtumor necrosis factor-α. The cells are incubated for an additional 24 hbefore the cells are harvested. At time of harvest, the spent media isremoved from the HUVECs and rinsed in 200 μL PBS. Cell lysis solution(70 μL) is then added the cells in each well and incubated for 5-10 minat room temperature, to allow for complete cell lysis and detachment.mRNA is then prepared using the “mRNA Catcher PLUS plate” (Invitrogen),according to the protocol supplied. After the last wash, as much washbuffer as possible is aspirated without allowing the wells to dry.Elution buffer (E3, 70 μL) is then added to each well. mRNA is theneluted by incubating the mRNA Catcher PLUS plate with elution buffer for5 min at 68° C. and then immediately placing the plate on ice.

The eluted mRNA so isolated is then used in a one-step quantitativereal-time PCR reaction, using components of the Ultra Sense Kit togetherwith Applied Biosystems primer-probe mixes. Real-time PCR data isanalyzed, normalizing the Ct values for hVCAM to an internal control,prior to determining the fold induction of each unknown sample, relativeto the control.

Example 7: Inhibition of hMCP-1 mRNA Transcription

In this example, hMCP-1 mRNA in human peripheral blood mononuclear cellsis quantitated to measure the transcriptional inhibition of hMCP-1 whentreated with a compound of the present disclosure.

Human Peripheral Blood Mononuclear Cells are plated (1.0×10⁵ cells perwell) in a 96-well plate in 45 μL RPMI-1640 containing 10% FBS andpenicillin/streptomycin. The cells are treated with the test compound(45 μL at 2× concentration), and then the cells are incubated at 37° C.for 3 h before the cells are harvested. At time of harvest, cells aretransferred to V-bottom plates and centrifuged (800 rpm, 5 min). Spentmedia is removed and cell lysis solution (70 μL) is added to the cellsin each well and incubated for 5-10 min at room temperature, to allowfor complete cell lysis and detachment. mRNA is then prepared using the“mRNA Catcher PLUS plate” (Invitrogen), according to the protocolsupplied. After the last wash, as much wash buffer as possible isaspirated without allowing the wells to dry. Elution buffer (E3, 70 μL)is then added to each well. mRNA is then eluted by incubating the mRNACatcher PLUS plate with Elution Buffer for 5 min at 68° C. and thenimmediately placing the plate on ice.

The eluted mRNA isolated is then used in a one-step quantitativereal-time PCR reaction, using components of the Ultra Sense Kit togetherwith Applied Biosystems primer-probe mixes. Real-time PCR data isanalyzed, normalizing the Ct values for hMCP-1 to an internal control,prior to determining the fold induction of each unknown sample, relativeto the control.

Example 8: Up-Regulation of hApoA-1 mRNA Transcription

In this example, ApoA-I mRNA in tissue culture cells was quantitated tomeasure the transcriptional up-regulation of ApoA-I when treated with acompound of the invention.

Huh7 cells (2.5×10⁵ per well) were plated in a 96-well plate using 100μL DMEM per well, (Gibco DMEM supplemented with penicillin/streptomycinand 10% FBS), 24 h before the addition of the compound of interest.After 48 h treatment, the spent media was removed from the Huh-7 cellsand placed on ice (for immediate use) or at −80° C. (for future use)with the “LDH cytotoxicity assay Kit II” from Abeam. The cells remainingin the plate were rinsed with 100 μL PBS.

Then 85 μL of cell lysis solution was added to each well and incubatedfor 5-10 min at room temperature, to allow for complete cell lysis anddetachment. mRNA was then prepared using the “mRNA Catcher PLUS plate”from Life Technologies, according to the protocol supplied. After thelast wash, as much wash buffer as possible was aspirated withoutallowing the wells to dry. Elution Buffer (E3, 80 μL) was then added toeach well. mRNA was then eluted by incubating the mRNA Catcher PLUSplate with Elution Buffer for 5 min at 68° C., and then 1 min at 4° C.Catcher plates with mRNA eluted were kept on ice for use or stored at−80° C.

The eluted mRNA isolated was then used in a one-step real-time PCRreaction, using components of the Ultra Sense Kit together with LifeTechnologies primer-probe mixes. Real-time PCR data was analyzed, usingthe Ct values, to determine the fold induction of each unknown sample,relative to the control (that is, relative to the control for eachindependent DMSO concentration).

Compounds with an EC₁₇₀ value less than or equal to 0.3 μM were deemedto be highly active (+++); compounds with an EC₁₇₀ value between 0.3 and3 μM were deemed to be very active (++); compounds with an EC₁₇₀ valuebetween 3 and 30 μM were deemed to be active (+).

TABLE 8 Up-regulation of hApoA-1 mRNA Transcription. Example CompoundApoA-1 activity 7 +++

Example 9: In Vivo Efficacy in Athymic Nude Mouse Strain of an AcuteMyeloid Leukemia Xenograft Model Using MV4-11 Cells

MV4-11 cells (ATCC) are grown under standard cell culture conditions and(NCr) nu/nu fisol strain of female mice age 6-7 weeks are injected with5×10⁵ cells/animal in 100 μL PBS+100 μL Matrigel in the lower leftabdominal flank. By approximately day 18 after MV4-11 cells injection,mice are randomized based on tumor volume (L×W×H)/2) of average ˜120mm³. Mice are dosed orally with compound at 75 mg/kg b.i.d and 120 mg/kgb.i.d in EA006 formulation at 10 mL/kg body weight dose volume. Tumormeasurements are taken with electronic micro calipers and body weightsmeasured on alternate days beginning from dosing period. The averagetumor volumes, percent Tumor Growth Inhibition (TGI) and % change inbody weights are compared relative to Vehicle control animals. Themeans, statistical analysis and the comparison between groups arecalculated using Student's t-test in Excel.

TABLE 9 In vivo efficacy in athymic nude mouse strain of an acutemyeloid leukemia xenograft model Example Compound In vivo activityExample 7 Active

Example 10: In Vivo Efficacy in Athymic Nude Mouse Strain of an AcuteMyeloid Leukemia Xenograft Model Using OCI-3 AML Cells

OCI-3 AML cells (DMSZ) were grown under standard cell culture conditionsand (NCr) nu/nu fisol strain of female mice age 6-7 weeks were injectedwith 10×10⁶ cells/animal in 100 μL PBS+100 μL Matrigel in the lower leftabdominal flank. By approximately day 18-21 after OCI-3 AML cellsinjection, mice were randomized based on tumor volume (L×W×H)/2) ofaverage 100-300 mm³. Mice were dosed orally with compound at 30 mg/kgb.i.d on a continuous dosing schedule and at 2.5 to 45 mg/kg q.d. on a 5day on and 2 day off dosing schedule in EA006 formulation at 10 mL/kgbody weight dose volume. Tumor measurements were taken with electronicmicro calipers and body weights measured on alternate days beginningfrom dosing period. The average tumor volumes, percent Tumor GrowthInhibition (TGI) and % change in body weights were compared relative toVehicle control animals. The means, statistical analysis and thecomparison between groups were calculated using Student's t-test inExcel.

Example 11: Evaluation of Target Engagement

MV4-11 cells (ATCC) are grown under standard cell culture conditions and(NCr) nu/nu fisol strain of female mice age 6-7 weeks are injected with5×10⁶ cells/animal in 100 μL PBS+100 μL Matrigel in the lower leftabdominal flank. By approximately day 28 after MV4-11 cells injection,mice are randomized based on tumor volume (L×W×H)/2) of average ˜500mm³. Mice are dosed orally with compound in EA006 formulation at 10mL/kg body weight dose volume and tumors harvested 6 hrs post dose forBcl2 and c-myc gene expression analysis as PD biomarkers.

Example 12: In Vivo Efficacy in Mouse Endotoxemia Model Assay

Sub lethal doses of Endotoxin (E. Coli bacterial lipopolysaccharide) areadministered to animals to produce a generalized inflammatory responsewhich is monitored by increases in secreted cytokines. Compounds areadministered to C57/BI6 mice at T=4 hours orally at 75 mg/kg dose toevaluate inhibition in IL-6 and IL-17 and MCP-1 cytokines post 3-hchallenge with lipopolysaccharide (LPS) at T=0 hours at 0.5 mg/kg doseintraperitoneally.

Example 13: In Vivo Efficacy in Rat Collagen-Induced Arthritis

Rat collagen-induced arthritis is an experimental model of polyarthritisthat has been widely used for preclinical testing of numerousanti-arthritic agents. Following administration of collagen, this modelestablishes a measurable polyarticular inflammation, marked cartilagedestruction in association with pannus formation and mild to moderatebone resorption and periosteal bone proliferation. In this model,collagen is administered to female Lewis strain of rats on Day 1 and 7of study and dosed with compounds from Day 11 to Day 17. Test compoundsare evaluated to assess the potential to inhibit the inflammation(including paw swelling), cartilage destruction and bone resorption inarthritic rats, using a model in which the treatment is administeredafter the disease has been established.

Example 14: In Vivo Efficacy in Experimental AutoimmuneEncephalomyelitis (EAE) Model of MS

Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediatedautoimmune disease of the CNS which shares many clinical andhistopathological features with human multiple sclerosis (MS). EAE isthe most commonly used animal model of MS. T cells of both Th1 and Th17lineage have been shown to induce EAE. Cytokines IL-23, IL-6 and IL-17,which are either critical for Th1 and Th17 differentiation or producedby these T cells, play a critical and non-redundant role in EAEdevelopment. Therefore, drugs targeting production of these cytokinesare likely to have therapeutic potential in treatment of MS.

Compounds of Formula I or Ia were administered at 50 to 125 mg/kg b.i.d.from time of immunization to EAE mice to assess anti-inflammatoryactivity. In this model, EAE is induced by MOG₃₅₋₅₅/CFA immunization andpertussis toxin injection in female C57BI/6 mice.

TABLE 10 In Vivo Efficacy in Experimental autoimmune encephalomyelitis(EAE) Model of MS Example Compound In vivo activity Example 7 Active

Example 15: Ex Vivo Effects on T Cell Function from Splenocyte andLymphocyte Cultures Stimulated with External MOG Stimulation

Mice were immunized with MOG/CFA and simultaneously treated with thecompound for 11 days on a b.i.d regimen. Inguinal Lymph node and spleenwere harvested, cultures were set up for lymphocytes and splenocytes andstimulated with external antigen (MOG) for 72 hours. Supernatants fromthese cultures were analyzed for TH1, Th2 and Th17 cytokines using aCytometric Bead Array assay.

Example 16: In Vivo Efficacy in Athymic Nude Mouse Strain of MultipleMyeloma Xenograft Model Using MM1.s Cells

MM1.s cells (ATCC) are grown under standard cell culture conditions and(NCr) nu/nu fisol strain of female mice age 6-7 weeks are injected with10×10⁶ cells/animal in 100 μL PBS+100 μL Matrigel in the lower leftabdominal flank. By approximately day 21 after MM1.s cells injection,mice are randomized based on tumor volume (L×W×H)/2) of average ˜120mm³. Mice are dosed orally with compound at 75 mg/kg b.i.d in EA006formulation at 10 mL/kg body weight dose volume. Tumor measurements aretaken with electronic micro calipers and body weights measured onalternate days beginning from dosing period. The average tumor volumes,percent Tumor Growth Inhibition (TGI) and % change in body weights arecompared relative to Vehicle control animals. The means, statisticalanalysis and the comparison between groups are calculated usingStudent's t-test in Excel.

Other embodiments of the present disclosure will be apparent to thoseskilled in the art from consideration of the specification and practiceof the present disclosure disclosed herein. It is intended that thespecification and examples be considered as exemplary only, with a truescope and spirit of the present disclosure being indicated by thefollowing claims.

1-104. (canceled)
 105. A compound of Formula IIc′″:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orhydrate thereof, wherein: the A-B bicyclic ring is optionallysubstituted with one or more groups independently selected fromdeuterium, —NH₂, amino, heterocycle(C₄-C₆), carbocycle(C₄-C₆), halogen,—CN, —OH, —CF₃, alkyl(C₁-C₆), thioalkyl(C₁-C₆), alkenyl(C₁-C₆), andalkoxy(C₁-C₆); D₁ is

X is selected from —CH₂— and —CH(CH₃)—; and R₄ is a phenyl ringoptionally substituted with groups independently selected fromdeuterium, alkyl(C₁-C₄), alkoxy(C₁-C₄), halogen, —CF₃, CN, and-thioalkyl(C₁-C₄), wherein each alkyl, alkoxy, and thioalkyl may beoptionally substituted with F, Cl, or Br.
 106. The compound according toclaim 105, or a stereoisomer, tautomer, pharmaceutically acceptablesalt, or hydrate thereof, wherein the A-B bicyclic ring is substitutedwith one or more groups independently selected from deuterium, methyl,and halogen.
 107. The compound according to claim 105, or astereoisomer, tautomer, pharmaceutically acceptable salt, or hydratethereof, wherein R₄ is a phenyl ring optionally substituted with one ormore of the following groups: alkyl(C₁-C₄) selected from methyl, ethyl,propyl, isopropyl, and butyl; alkoxy(C₁-C₄) selected from methoxy,ethoxy, and isopropoxy; halogen selected from F and Cl; andthioalkyl(C₁-C₄) selected from —SMe, —SEt, —SPr, and —SBu.
 108. Thecompound according to claim 106, or a stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof, wherein R₄ is aphenyl ring optionally substituted with one or more of the followinggroups: alkyl(C₁-C₄) selected from methyl, ethyl, propyl, isopropyl, andbutyl; alkoxy(C₁-C₄) selected from methoxy, ethoxy, and isopropoxy;halogen selected from F and Cl; and thioalkyl(C₁-C₄) selected from —SMe,—SEt, —SPr, and —SBu.
 109. The compound according to claim 105, or astereoisomer, tautomer, pharmaceutically acceptable salt, or hydratethereof, wherein R₄ is phenyl or 4-methoxyphenyl.
 110. The compoundaccording to claim 106, or a stereoisomer, tautomer, pharmaceuticallyacceptable salt, or hydrate thereof, wherein R₄ is phenyl or4-methoxyphenyl.
 111. The compound according to claim 105, selectedfrom:4-amino-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one;4-amino-1-(4-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one;4-amino-6-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxybenzyl)-1H-benzo[d]imidazol-2(3H)-one;4-amino-6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one;4-amino-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one;(S)-4-amino-6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one;and(R)-4-amino-6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one,or a stereoisomer, tautomer, pharmaceutically acceptable salt, orhydrate thereof.
 112. A pharmaceutical composition comprising a compoundof claim 105 or a stereoisomer, tautomer, pharmaceutically acceptablesalt, or hydrate thereof, and a pharmaceutically acceptable carrier.113. A pharmaceutical composition comprising a compound of claim 106 ora stereoisomer, tautomer, pharmaceutically acceptable salt, or hydratethereof, and a pharmaceutically acceptable carrier.
 114. A method fortreating a disease or disorder selected from an autoimmune disease ordisorder, an inflammatory disease or disorder, a cancer, a benignproliferative or fibrotic disorder, a cardiovascular disease ordisorder, a metabolic disease or disorder, HIV, and a neurologicaldisease or disorder, comprising administering a therapeuticallyeffective amount of a compound or a stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof according to claim105.
 115. The method according to claim 114, wherein the autoimmunedisease or disorder is selected from Acute DisseminatedEncephalomyelitis, Agammaglobulinemia, Allergic Disease, Ankylosingspondylitis, Anti-GBM/Anti-TBM nephritis, Anti-phospholipid syndrome,Autoimmune aplastic anemia, Autoimmune hepatitis, Autoimmune inner eardisease, Autoimmune myocarditis, Autoimmune pancreatitis, Autoimmuneretinopathy, Autoimmune thrombocytopenic purpura, Behcet's Disease,Bullous pemphigoid, Castleman's Disease, Celiac Disease, Churg-Strausssyndrome, Crohn's Disease, Cogan's syndrome, Dry eye syndrome, Essentialmixed cryoglobulinemia, Dermatomyositis, Devic's Disease, Encephalitis,Eosinophlic esophagitis, Eosinophilic fasciitis, Erythema nodosum, Giantcell arteritis, Glomerulonephritis, Goodpasture's syndrome,Granulomatosis with Polyangiitis (Wegener's), Graves' Disease,Guillain-Barre syndrome, Hashimoto's thyroiditis, Hemolytic anemia,Henoch-Schonlein purpura, IgA nephropathy, Inclusion body myositis, TypeI diabetes, Interstitial cystitis, Kawasaki's Disease, Leukocytoclasticvasculitis, Lichen planus, Systemic lupus erythematosus (SLE),Microscopic polyangitis, Multiple sclerosis, Myasthenia gravis,myositis, Optic neuritis, Pemphigus, POEMS syndrome, Polyarteritisnodosa, Primary biliary cirrhosis, Psoriasis, Psoriatic arthritis,Pyoderma gangrenosum, Relapsing polychondritis, Rheumatoid arthritis,Sarcoidosis, Scleroderma, Sjogren's syndrome, Takayasu's arteritis,Transverse myelitis, Ulcerative colitis, Uveitis, and Vitiligo.
 116. Themethod according to claim 114, wherein the inflammatory disease ordisorder is selected from sinusitis, pneumonitis, osteomyelitis,gastritis, enteritis, gingivitis, appendicitis, irritable bowelsyndrome, tissue graft rejection, chronic obstructive pulmonary disease(COPD), septic shock, toxic shock syndrome, SIRS, bacterial sepsis,osteoarthritis, acute gout, acute lung injury, acute renal failure,burns, Herxheimer reaction, and SIRS associated with viral infections.117. The method according to claim 114, wherein the disease or disorderis a cancer.
 118. The method according to claim 117, wherein the canceris selected from B-acute lymphocytic leukemia, Burkitt's lymphoma,diffuse large cell lymphoma, multiple myeloma, primary plasma cellleukemia, atypical carcinoid lung cancer, bladder cancer, breast cancer,cervix cancer, colon cancer, gastric cancer, glioblastoma,hepatocellular carcinoma, large cell neuroendocrine carcinoma,medulloblastoma, melanoma, nodular melanoma, neuroblastoma, esophagealsquamous cell carcinoma, osteosarcoma, ovarian cancer, prostate cancer,renal clear cell carcinoma, retinoblastoma, rhabdomyosarcoma, small celllung carcinoma, NUT midline carcinoma, B-cell lymphoma, non-small celllung cancer, head and neck squamous cell carcinoma, chronic lymphocyticleukemia, follicular lymphoma, diffuse large B cell lymphoma withgerminal center phenotype, Hodgkin's lymphoma, activated anaplasticlarge cell lymphoma, primary neuroectodermal tumor, pancreatic cancer,adenoid cystic carcinoma, T-cell prolymphocytic leukemia, malignantglioma, thyroid cancer, Barret's adenocarcinoma, hepatoma,pro-myelocytic leukemia, and mantle cell lymphoma.
 119. The methodaccording to claim 117, wherein the cancer: (a) exhibits overexpression,translocation, amplification, or rearrangement of a myc familyoncoprotein; (b) results from aberrant regulation of BET proteins; (c)relies on pTEFb (Cdk9/cyclin T) and BET proteins to regulate oncogenes;(d) is associated with upregulation of BET responsive genes CDK6, Bcl2,TYRO3, MYB, and/or hTERT; and/or (e) is associated with a viralinfection.
 120. The method according to claim 119, wherein the cancerexhibits overexpression, translocation, amplification, or rearrangementof a myc family oncoprotein and is selected from B-acute lymphocyticleukemia, Burkitt's lymphoma, Diffuse large cell lymphoma, Multiplemyeloma, Primary plasma cell leukemia, Atypical carcinoid lung cancer,Bladder cancer, Breast cancer, Cervix cancer, Colon cancer, Gastriccancer, Glioblastoma, Hepatocellular carcinoma, Large cellneuroendocrine carcinoma, Medulloblastoma, Nodular melanoma, Superficialspreading melanoma, Neuroblastoma, Esophageal squamous cell carcinoma,Osteosarcoma, Ovarian cancer, Prostate cancer, Renal clear cellcarcinoma, Retinoblastoma, Rhabdomyosarcoma, and Small cell lungcarcinoma.
 121. The method according to claim 119, wherein the cancerresults from aberrant regulation of BET proteins and is selected fromNUT midline carcinoma, B-cell lymphoma, non-small cell lung cancer,esophageal cancer, head and neck squamous cell carcinoma, and coloncancer.
 122. The method according to claim 119, wherein the cancerrelies on pTEFb (Cdk9/cyclin T) and BET proteins to regulate oncogenesand is selected from chronic lymphocytic leukemia, multiple myeloma,follicular lymphoma, diffuse large B cell lymphoma with germinal centerphenotype, Burkitt's lymphoma, Hodgkin's lymphoma, anaplastic large celllymphoma, neuroblastoma, primary neuroectodermal tumor,rhabdomyosarcoma, prostate cancer, and breast cancer.
 123. The methodaccording to claim 119, wherein the cancer is associated withupregulation of BET responsive genes CDK6, Bcl2, TYRO3, MYB, and/orhTERT and is selected from pancreatic cancer, breast cancer, coloncancer, glioblastoma, adenoid cystic carcinoma, T-cell prolymphocyticleukemia, malignant glioma, bladder cancer, medulloblastoma, thyroidcancer, melanoma, multiple myeloma, Barret's adenocarcinoma, hepatoma,prostate cancer, pro-myelocytic leukemia, chronic lymphocytic leukemia,mantle cell lymphoma, diffuse large B-cell lymphoma, small cell lungcancer, and renal carcinoma.
 124. The method according to claim 119,wherein the cancer is associated with a viral infection selected fromEpstein-Barr Virus, hepatitis B virus, hepatitis C virus, Kaposi'ssarcoma associated virus, human papilloma virus, Merkel cellpolyomavirus, and human cytomegalovirus.
 125. The method according toclaim 114, wherein the compound or a stereoisomer, tautomer,pharmaceutically acceptable salt, or hydrate thereof is administered incombination with another anticancer agent.
 126. The method according toclaim 125, wherein the anticancer agent is selected from ABT-737,Azacitidine (Vidaza®), AZD1152 (Barasertib), AZD2281 (Olaparib), AZD6244(Selumetinib), BEZ235, Bleomycin Sulfate, Bortezomib (Velcade®),Busulfan (Myleran®), Camptothecin, Cisplatin, Cyclophosphamide(Clafen®), CVT387, Cytarabine (AraC), Dacarbazine, DAPT (GSI-IX),Decitabine, Dexamethasone, Doxorubicin (Adriamycin®), Etoposide,Everolimus (RAD00I), Flavopiridol (Alvocidib), Ganetespib (STA-9090),Gefitinib (Iressa®), Idarubicin, Ifosfamide (Mitoxana), IFNa2a (Roferon®A), Melphalan (Alkeran®), Methazolastone (temozolomide), Metformin,Mitoxantrone (Novantrone®), Paclitaxel, Phenformin, PKC412(Midostaurin), PLX4032 (Vemurafenib), Pomalidomide (CC-4047), Prednisone(Deltasone®), Rapamycin, Revlimid® (Lenalidomide), Ruxolitinib(INCB018424), Sorafenib (Nexavar®), SU11248 (Sunitinib), SU11274,Vinblastine, Vincristine (Oncovin®), Vinorelbine (Navelbine®),Vorinostat (SAFIA), and WP1130 (Degrasyn).